The 2024 edition of MCR (Medicinal Chemistry Reviews), edited by Joachim Rudolph and Will Watkins, has just been published by the American Chemical Society MEDI Division. Featuring contributions from a global team of section editors and authors, MCR offers concise updates on a broad range of contemporary drug discovery topics, making it an invaluable resource for both aspiring and experienced medicinal chemists.

DILI is a leading cause of acute liver failure, accounting for half of these cases and often resulting in drug withdrawals. Understanding and managing DILI risk as a medicinal chemist involves exploring the intricate interplay among properties and structural features. In this article, we provide a medicinal chemist's perspective on the current understanding of DILI mechanisms, highlight cutting-edge assay developments for a holistic assessment, and discuss strategies for predicting DILI risks.

One of the key challenges in CNS projects is achieving sufficient unbound brain exposure to engage the target. To predict CNS exposure, scientists employ metrics like CNS MPO scores from Pfizer and Merck, Bayesian models, and methods for balancing physicochemical properties. However, these in silico metrics often fail to correlate well with experimental data. Schrödinger's team has discovered the energy of solvation (E-sol) metric, which accurately predicts Kp,uu and has been validated with CNS-penetrant DLK inhibitors. Explore more in this detailed Drug Hunter article.

Imagine having access to an almost infinite amount of chemical space that could include the next blockbuster medicine waiting to be discovered. The challenge for medicinal chemists is balancing the exploration of this vast space in early drug discovery with the need for focused exploration in later stages. This article explores the genesis of a new AI-powered drug design tool, AIDDISON™ from MilliporeSigma, and how this platform can benefit discovery teams around the world.

Drug Hunter has sifted through news articles, press releases, financial disclosures, SEC filings and more to bring you a roundup of 2023's biggest mergers and acquisitions (M&A) in the drug discovery world. In this 4-part series we will give you an open-access overview of the M&A landscape, and then for Drug Hunter members in the coming weeks, we will be providing in-depth coverage and analysis of the small molecule-focused (parts 2 & 3) and biologics-based deals (part 4). This premium content includes background on the targets, chemical/biological matter and clinical data driving these deals.

Peptidic GLP-1R agonists have received significant media coverage over the past year for their astounding efficacy in several indications. While most of the recent fanfare has been related to their role in weight loss, GLP-1R agonists have been a mainstay of the type 2 diabetes treatment landscape for the past 2 decades. GLP-1R agonists have also recently shown efficacy in reducing heart disease risk and treating certain chronic kidney diseases. Here’s a recap of the March 14th, 2024, Flash Talk, from Oliver Philps.

If you are as excited as we are about this new era of non-opioid pain management and want to learn more, explore our series of articles that unravel the fascinating history of target validation of voltage-gated sodium channels, showcase the breakthroughs achieved so far, and look forward to what lies ahead for the industry.

Drug Hunter offers industry professionals a faster way to find and absorb the latest research and insights in drug discovery. It is a curated collection of the most relevant and transferable scientific knowledge so you can spend less time weeding through the noise and more time turning molecules into medicines. But we also love hearing from you, the drug hunters in the field.

The "New Drugs on the Horizon" sessions at the AACR Annual Meeting 2024 in San Diego revealed twelve innovative oncology agents and offered attendees a first look at their structures and preliminary data as they enter/progress in the clinic. In case you missed any of these exciting compounds – including selective CDK inhibitors, molecular glues, bifunctional degraders, a radiopharmaceutical, a bifunctional antibody, and an ADC – this article covers the structures and targets disclosed. A separate session disclosed the structure of a pan-RAS isoform inhibitor with remarkable clinical results.

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2023, and the results are in. The 2023 winner, with the most votes between ten molecules, is Merck’s oral macrocyclic peptide inhibitor of PCSK9, MK-0616, derived from mRNA display technology and shown to have clinical efficacy. Herein, we highlight what makes MK-0616 so impressive to the drug discovery community.

The highly anticipated First Time Disclosures session at the ACS Spring 2024 Meeting in New Orleans, organized by Nicole Goodwin and H. Rachel Lagiakos, presented a variety of new orally available small molecules. In case you missed any of these exciting molecules, from Oric’s CD73 inhibitor to Deciphera’s first-in-class ULK1/2 inhibitor, this article provides the structures and targets for the novel molecules disclosed at the session.

The team reviews hundreds of compounds from thousands of papers, press releases, and other sources each month to select candidates for Molecules of the Month. Here we have compiled a table of >70 additional molecules that were of interest in January 2024 along with highlights from some of our favorites, including molecules targeting SOS1, NLRP3, SMARCA2, and more.

With increasingly tight timelines between bench and clinic, considering formulation strategies early on can give your program a competitive edge. This succinct formulations guide provides specific clinically-used examples of common formulations, and can help you select a formulation strategy most likely to succeed based on the properties of your compound.

The impact of small and mid-sized biotech companies has become increasingly important. The shift from large pharma dominance to a biotech-driven era of drug discovery presents challenges to the traditional model of education for emerging medicinal chemists. Industry leader Dean Brown recently highlighted challenges for modern medicinal chemists starting in biotech who face fewer mentoring opportunities and are often propelled into leadership positions sooner than their counterparts in big pharma. Here we share how our team of former industry scientists at Drug Hunter can help.

Among the small molecule highlights in January’s news were a $100M+ Series A for a PARP1 + PI3Kα-focused company, clinical data with an SLC inhibitor for PKU, a 5-HT2C superagonist for seizures, and a NK1,3 dual antagonist for women’s health. A novel anti-obesity agent from phenotypic screening also made headlines, and the close of a major acquisition may bring relief to the industry. You can read about these notable scientific highlights and more below.

The Drug Hunter team is piloting a new series highlighting notable disclosures in the patent literature to provide our readers a timely and scientifically flavorful synopsis of therapeutic targets being actively pursued, emerging industry breakthroughs, and fascinating chemical matter. Here we highlight 12 patents published in December 2023 that piqued our interest, and compiled a searchable table comprising key information from more than 180 additional patents of potential interest to drug hunters. If you have any suggestions on how to make this more useful, please let us know!

The team reviews hundreds of compounds from thousands of papers, press releases, and other sources each month to select candidates for Molecules of the Month. Here we have compiled a table of >60 additional molecules that were of interest in December 2023 along with highlights from some of the team’s favorites in the article.

The final set of Molecules of the Month for 2023 is out, and now it’s time to nominate your favorite molecules for 2023’s Molecules of the Year! Nominees should have either been first disclosed in 2023 or had a major new update in 2023 (e.g. clinical trial readout, publication, business transaction, approval). The molecule must have a [...]

Momelotinib is a JAK inhibitor approved by the FDA in September 2023 for treating myelofibrosis. Last year, the molecule’s co-inventors, Andrew Wilks and Christopher Burns, gave a Drug Hunter Flash talk about the development of this drug with a fascinating mechanism of action.

In celebration of the molecule’s advancement, here we recap their brilliant story, including Wilks’ discovery of the JAK kinases and how he gave them their name, and the long, sometimes fraught journey of momelotinib through several companies before its acquisition and commercialization by GSK.

The 34 small molecule drug approvals of 2023 are summarized in this poster and article with the structures, mechanisms of action, originators (& marketers), indications, and links to deep-dive reviews and more information about each drug.

2023 was an incredible year in drug discovery. Drug Hunter featured many remarkable case studies last year including campaigns on challenging targets like KRAS, programs employing emerging modalities like degraders or oral macrocyclic peptides, and compounds with fascinating properties like allostery and mutant-selectivity. In case you missed these stories, here are the top 12 most popular Drug Hunter case studies published in 2023.

Drug Hunter regularly reviews trends and topics of industry interest, from hot new molecules from conferences to recently notable targets and technologies. Here are ten of the most popular reviews accessed on Drug Hunter in 2023.

The educational and professional resources on Drug Hunter are meant to help you with your job on a regular basis. Here are the ten most popular resource pages on Drug Hunter in 2023 - if you haven’t found and used these already, check them out!

In a Drug Hunter Flash Talk, Dennis Koester, Director of Medicinal Chemistry at FibroGen, shared an adage credited to the Greek philosopher Epictetus that he wishes his younger self had learned: "We have two ears and one mouth so that we can listen twice as much as we speak." During this ongoing video series, other scientists, including Chris Burns, Christian Gampe, Katrina (Kate) Jackson, Dafydd Owen, Prof. Richard (Rick) Silverman, and Prof. Andrew Wilks, also talked about what they wished they had learned earlier in their careers.

With initial signs of efficacy and tolerability, Drug Hunter has launched Phase III! To address your helpful feedback, we’ve rebuilt the platform from scratch to support new features and enhancements. We appreciate your patience with the rollout!

In Wednesday’s Flash Talk webinar, we covered recent highlights in covalent drug discovery, with lots of great questions from the audience. The webinar and recording are available below to everyone thanks to our sponsor, Revvity Signals, and the slides are available for download to Premium members at the bottom.

Genentech’s GDC-6599 is the first oral TRP Ankyrin 1 (TRPA1) antagonist to reach Ph. IIa (NCT05660850) for chronic cough after preclinical studies and a Ph. I trial showed it was well-tolerated, in contrast to prior molecules. The transient receptor potential (TRP) family of ion channels has been the subject of intensive drug discovery efforts due to their critical role in the development and progression of pain, itch, and respiratory conditions.

Understanding how a small molecule ligand binds to its target is valuable in drug discovery, because it enables more efficient optimization through structure-based design, better mechanistic understanding of molecular pharmacology, and greater confidence in the therapeutic hypothesis from both safety and efficacy perspectives. Recently, Drug Hunter highlighted methods for target identification when the target is unknown.

The First Disclosures sessions at the 2023 ACS Fall Meeting in San Francisco, organized by Nikki Goodwin, presented a variety of new orally available small molecules. The standing room-only sessions were so highly attended that many attendees were unfortunately kicked out due to the fire code.

To help drug discovery professionals get the most out of your trip to ACS San Francisco 2023, we compiled a table of sessions that are likely to be of high interest to industry scientists here.

Targeted Protein Degradation (TPD) allows for elimination, rather than inhibition, of proteins by exploiting cells’ own protein clearance mechanisms. While traditional inhibitors can be very effective at preventing a protein from undertaking a particular function, blocking protein activity...

Small molecule drugs make up most of the drugs we take conveniently as pills, including painkillers like ibuprofen (Advil), antibiotics like penicillin and amoxicillin, or cholesterol-lowering drugs like atorvastatin (Lipitor). The biotechnology revolution allowed scientists to create drugs through genetic engineering and related biological processes, creating a new category of drugs known as “biologics.”...

Macrocyclic molecules, containing 12 or more atoms in a ring system, are increasingly prevalent in drug discovery, with over 67 macrocyclic drugs approved so far and several notable examples of clinical success highlighted on Drug Hunter recently, including MK-0616 , repotrectinib , and pacritinib . By imparting conformational restraint and [...]

Dian Su’s journey from chemistry and proteomics to the DMPK of drug conjugates Following a different path comes naturally to Dian Su, Senior Director of DMPK at Bicycle Therapeutics. From a childhood in a small village in China’s northeast Shandong province to her work examining the drug metabolism and pharmacokinetics (DMPK) of antibody-drug [...]

Here’s a common scenario - your team has just completed a phenotypic screening campaign, cleaned out the false positives through hit triage , and now you have modestly optimized validated leads with cell-based activity. The problem is, you have no idea how your compounds work, and whether they act on a target or set of targets that are worth [...]

A significant section of the Inflation Reduction Act (H.R. 5376) recently signed into law was targeted at lowering public spending on prescription drugs (Subtitle B: Prescription Drug Pricing Reform). The new laws include Medicare negotiation and includes a provision that disproportionately affects small molecules which have triggered [...]

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2022, and the results are in. The 2022 winner, with the most overall votes across the ten finalist molecules , is BMS’ oral, deuterated allosteric TYK2 inhibitor, deucravacitinib, the first new treatment for plaque psoriasis in nearly a decade [...]

April 1st, 2023 - Molecule of the Day: Curcumin Curcumin is a component of tumeric, and is sold as an herbal supplement, cosmetics ingredient, food flavoring, and food coloring. The molecule is one of the most widely studied therapeutics in history, with papers, reviews, patents, and other sources citing its potential for treating cancer [...]

While the Molecules of the Month are being selected and our deep dive reviews are being prepared, you can find early highlights from our team’s journal club from February 2023. Check out AstraZeneca’s preclinical SERD, Merck’s Ph. I c-KIT inhibitor, University of Michigan’s STAT5 PROTAC degrader, and more snippets to jumpstart your reading [...]

Here’s a preview of two molecules acquired in January 2023 among 14 mentioned in this article: deuruxolitinib (CTP-543) This molecule, a deuterated version of JAK1/2 inhibitor ruxolitinib (Opzelura, Incyte), has received Breakthrough Therapy designation from the FDA and is being acquired by Sun Pharma via Concert in a $0.576B transaction [...]

We recently explored how the lipophilicity (logP) of drugs has changed over time and found that, on average, drugs have become more lipophilic through the decades, primarily attributable to the industry’s move away from natural products. Despite this shift, it is clear from a broad qualitative comparison of structures from past decades to [...]

Two past Molecules of the Month inductees had significant updates recently, showing they’re still moving forward: upacicalcet This September ‘22 Molecule of the Month is an IV calcium-sensing receptor (CaSR) agonist first identified in flavor studies of peptides. It is already approved in Japan for secondary hyperparathyroidism (SHPT), and [...]

Our latest roundup of small molecules in the news includes three molecules moving into development for the first time: MRTX1133 Mirati’s reversible, long-acting KRASG12D inhibitor, and December ‘21 Molecule of the Month, is going into the clinic as an oral compound. While initial disclosures referred to its potential as an IV agent, Mirati [...]

The final set of Molecules of the Month for 2022 is out, and now it’s time to nominate your favorite molecules for 2022’s Molecules of the Year! Nominees should have either been first disclosed in 2022 or had a major new update in 2022 (e.g. clinical trial readout, publication, business transaction, approval). The molecule must have a [...]

You can download our compilation of the 10 first-in-class large molecule drug approvals from 2022 below, which includes structural illustrations, drug targets and mechanisms of action, doses and routes of administration, and indication.

In 2022 there were 36 novel small molecule and large molecule drugs approved by the FDA, including 19 small molecule drug approvals. You can download our compilation of all 19 small molecule drug approvals from 2022 below, which includes structures, drug targets and mechanisms of action, doses and routes of administration, and indication. You [...]

Artificial Intelligence (AI) is revolutionizing data processing, with applications to drug discovery ranging from automating cellular imaging to modeling protein folding . Although numerous startups are developing methods to apply AI-driven drug discovery to develop proprietary assets, a remaining challenge is making these powerful tools [...]

Since the 2014 discoveries that thalidomide-like compounds “glue” together the cereblon (CRBN) unit of the ubiquitin E3 ligase complex and certain immune cell transcription factors, molecular glue degraders have been caught up in the targeted protein degradation zeitgeist that catapulted PROTACs , their bulkier bivalent counterparts, to the [...]

Today, ozanimod is a likely megablockbuster drug approved for ulcerative colitis and multiple sclerosis. But before it became the first S1P modulator approved in ulcerative colitis, it received a scary, headline-making “ Refuse to File ” letter from the FDA due to insufficient preclinical characterization of an active metabolite RP112273 [...]

Drug lipophilicity is a core property that contributes to drug solubility, permeability, metabolic disposition, and other key properties. Increasing lipophilicity can often lead to increased affinity in relevant biological assays due to the hydrophobic nature of many protein binding pockets,  but this may also increase promiscuity to [...]

In a recent webinar , we surveyed our audience and were surprised to see that a significant majority of attendees thought the application of artificial intelligence and machine learning (AI/ML) methods was the most exciting area for drug discovery, beyond even degraders or molecular glues. Machine learning methods have been increasingly [...]

At AAPS 2022, I hosted a symposium where Ovoca Bio plc's Head of Research, Mikhail Lomonosov told us about orenetide. Orenetide is an internationally approved peptide drug for hypoactive sexual desire disorder (HSDD) (think Viagra for women). It appears to work within a few weeks in humans with a solid safety profile - Mikhail noted that one [...]

Drug candidates exhibiting atropisomerism are often considered challenging for development by pharmaceutical professionals from synthetic and regulatory perspectives. Molecules that exist as stable atropisomers can be acceptable for development, but are often difficult to synthesize in their isomerically pure form. Modern catalysis [...]

The real magic happens when chemists can integrate computational models into their assay cascades, thanks to trust in their predictions. To get there, grounding computational predictions in physics and experimental reality makes all the difference. In this article, Abba E. Leffler, Ph.D. from Schrödinger tells us about: How to make [...]

This edition of Drug Hunter Letters highlights recent insightful communications from Drug Hunter readers, including: Simon Bury on the History of GSK’s Recently Acquired $1.9B JAK Inhibitor Callie Bryan and Bryan McKibben on Insulin Receptor Partial Agonists and Recent Oncology Highlights Jesse Keicher on CXCR1/2 Antagonists in Treating [...]

This year’s EFMC-ISMC conference in Nice, France, had a fantastic collection of talks. Among the highlights were the two First Disclosure sections, where companies shared the structures of their latest clinical candidates for the first time. Many thanks to Dr. Julien Lefranc , one of our featured reviewers , for sharing his notes on these [...]

This article explains what Phase II drug metabolism is, contains a poster summarizing common enzyme-mediated bioconjugation reactions, and provides interesting examples of Phase II transformations and their impact on drug pharmacology. "As any biotransformation scientist will know, metabolism is not a binary function, and drugs can be cleared [...]

We're here at ACS Chicago 2022, covering sections of particular interest to drug discovery scientists. Among the highlights are the First Disclosures sections, where companies are sharing structures of clinical candidates for the first time. We'll go more in-depth into the science from the conference soon - for now, here's a high-level [...]

How a Follow-on Drug Can Create Value After a First-in-Class Drug Novel drugs can make a big impact in two main ways—by being first-in-class (FIC) or by being best-in-class (BIC). A novel drug that produces its therapeutic effect by interacting with a new target or that is used to treat a new condition is considered first-in-class (FIC) [...]

As biotech experts, risk taking is part of our business model. Without scientific and business risk, inventions would not occur and businesses would not grow. How do we know we are taking appropriate risks at the right time? How do we know we are using agile drug development strategies by tracking, understanding, and mitigating risk as our [...]

In this guest article, Dr. Luíza Cruz breaks down the synthesis of Gilead’s lenacapavir (GS-6207), Drug Hunter’s Small Molecule of the Year – 2020 . Lenacapavir is a promising first-in-class, long-acting injectable (LAI) HIV capsid inhibitor . Interesting synthetic steps employed in this route include an unusual sodium chlorite-mediated [...]

Product development is unique in biopharma in the degree of separation between product developers (R&D scientists) and end users (patients and practitioners). While R&D focuses on questions like “Is it possible to treat this disease?” and “How can we drug this target?”, commercial organizations focus on questions like “Why does a physician [...]

Optimizing lead compounds to have drug candidate-like qualities is time-consuming and expensive. Oftentimes, critical drug discovery project questions, such as on-target pharmacology or toxicology, can be answered more efficiently with compounds that are "good enough," saving teams time and further resource investment. This article discusses [...]

In this article, we highlight the importance of p K a values in medicinal chemistry and drug discovery and provide a reference poster of p K a values of common amines’ conjugate bases. Since amines are often a part of marketed drugs, knowledge of their p K a s can provide guidance in the selection of basic moieties to match the desired [...]

In the early 90’s, Wayne (Haifeng) Tang and Ray Zhao formed a friendship in high school in China. They were both stellar students in chemistry, and each was one of the country’s fraction of a percent to ace the notoriously difficult college entrance exams to land in China’s best universities. Wayne moved to the University of Science and [...]

We reviewed all of the biotech mergers and acquisitions in 2021 and did a deep dive on the list of biotech M&A transactions focused on drug discovery. In this series, we provide a high level overview of: The drug discovery biotech acquisitions by total consideration in 2021 The lead molecules in each acquisition and their structural [...]

with Julien Lefranc We asked one of our reviewers, Julien Lefranc , about what inspires and excites him about drug discovery. Here, he tells us about an unexpected, moving connection with a cancer patient, and what drives him to work every day. About Julien Julien is a Principal Scientist at Merck KGaA in Darmstadt and is a member of the [...]

Our first South San Francisco Drug Hunter event was so much fun, we've decided to host in-person events all over the world. The next few events will be networking mixers, but stay tuned for scientific symposia and conferences! Sign up here to get invites to future in-person events around the world, including in Boston, Basel, San Diego [...]

Thank you to all of the drug hunters who attended our second drug discovery webinar! You can find the video and slides at the bottom of this page. In part II of this series we covered: Emerging startups, growing drug discovery companies, and IPOs Clinical readouts, positive and negative Big deals and major regulatory actions Check out part [...]

In this highlight, Dr. Dennis C. Koester reviews treatment options for HIV and explains how small molecule long-acting injectables (LAIs) are offering significant promise in both HIV treatment and prophylaxis. A Coming Paradigm Shift for HIV Treatment and Prophylaxis By Dennis C. Koester The surge of the coronavirus pandemic has made our [...]

In this minireview, Dr. Romyr Dominique introduces three key concepts in fragment-based drug discovery and shares his favorite articles and resources on fragment-based drug discovery. Fragment-based drug discovery has emerged as a key tool for acquiring starting points for challenging targets like KRAS. By Dr. Romyr Dominique What is FBDD, or [...]

The gem-dimethylcyclopropyl group is a key element in drugs, candidates, and agrochemicals, with a recent example being nirmatrelvir, the active ingredient in the Pfizer COVID-19 drug, Paxlovid. Here, we review synthetic strategies used to produce the key gem-dimethylcyclopropylproline intermediate, which may now be required in hundred-ton [...]

In this minireview, Drs. Jayme L. Dahlin and Michael A. Walters summarize the different mechanisms by which molecules can be AICs (assay interference compounds), a subset of which can be flagged as PAINS (pan-assay interference compounds) by a popular set of substructure filters. They bin these into non-technology-related interference [...]

Recently, Dr. Alf Claesson (CEO of Awametox AB, inventor of SpotRM, and previously Principal Scientist and Section Head at AstraZeneca/Astra AB, Sweden) reached out about our resource on the bioactivation of structural alerts . Dr. Claesson shared the helpful notes that: carboxylic acids forming thioesters with CoA might be a greater danger [...]

It was great to see over 100 drug hunters at our first drug discovery webinar! You can find the video and slides at the bottom of this page. The scope of this talk grew to be a bit massive as we were planning it, so we decided to split it into two parts. This first part covered: Interesting tidbits from 2022 Q1's drug approvals Cool facets [...]

In this article, Dr. Thuy Tran , a CMC Project Leader at Servier, gives us a quick explanation of what an IND is, what a clinical hold is, and why clinical holds happen for drug discovery scientists. What is an IND? Health authorities require drug developers to provide and justify safety and efficacy information for new treatments in humans [...]

This page contains Drug Hunter's practical PK calculators useful for day-to-day drug discovery, including a PK unit converter such as for uM to ng/mL unit conversion, an animal study requirement calculator for how much material to synthesize in preparation for animal studies, and a simple human equivalent dose estimator . Who doesn't find [...]

Small-molecule drug candidates are increasingly falling “ beyond the rule of 5 ,” making oral administration more challenging. Optimizing a drug’s solid form can improve its solubility and bioavailability when further molecular modifications are prohibitive. This minireview covers solid form strategies for increasing the solubility and oral [...]

One of the privileges that have come with building Drug Hunter has been all the insightful thoughts and commentary our readers share. We also appreciate how readers help catch mistakes and offer corrections. This new series of “ Drug Hunter Letters” highlights recent insightful communications from drug hunters, which includes this time: Dr [...]

There were six small molecule candidates disclosed on Apr. 10th at AACR New Orleans 2022 at the New Drugs on the Horizon session, with another four on Apr. 11th. The New Drugs on the Horizon session is organized by the Chemistry in Cancer Research (CICR) Working Group , this year chaired by Joachim Rudolph . Thanks to reviewer Julien Lefranc [...]

It’s always nice to see a small molecule making the front page of the news , especially when it’s a Molecule of the Month from last year! Pfizer and ReViral announced an agreement for Pfizer to acquire ReViral for up to $525 million, including milestones (amount upfront not disclosed). ReViral’s lead molecule sisunatovir, is an oral [...]

The ACS first disclosures from ACS Spring 2022 MEDI section included six molecules, summarized below. Together with industry veteran Jesse Keicher , we put these molecules in context, exploring what makes each molecule interesting to drug hunters beyond what was shared at the conference. The first disclosures were: AMG 650, Amgen’s kinesin [...]

This article explains what Phase I drug metabolism is, contains a poster summarizing common enzyme-mediated drug metabolism reactions, and provides interesting examples of phase I biotransformations and their impact on drug pharmacology. By Drake Anthony Russell , reviewed by Dr. Dian Su and Dr. Julia Shanu-Wilson. Thanks to Hypha Discovery [...]

We asked the global drug discovery community to nominate and vote on their favorite molecule from 2021, and the results are in. The 2021 choice for Drug Hunter’s Small Molecule of the Year is Pfizer’s CoV-2 M pro Inhibitor, PF-07321332 (nirmatrelvir, Paxlovid) . Published in a November 2021 Science article , the molecule was praised for its [...]

GSK3640254, one of January 2022's Molecules of the Month , is an HIV maturation inhibitor and Ph. IIb clinical candidate (60-180 mg PO QD) with activity against a range of HIV strains with Gag polymorphisms. The first HIV maturation inhibitor to read out clinically was bevirimat (Myriad Genetics), derived from a natural product first [...]

The FDA recently approved Agios' Pyrukynd (mitapivat, AG-348) , a first-in-class, allosteric activator of pyruvate kinase (PK), for treatment of hemolytic anemia in adults with the genetic condition, pyruvate kinase deficiency. The drug is given orally with a starting dose of 5 mg BID, titrating up to 50 mg BID depending on hemoglobin (Hb) [...]

Contrary to popular belief, pharma is incredibly competitive, with dozens of companies often working on the same hot target at the same time. What sets pharma apart from the outside world though, is how deeply we respect our competitors and other scientists when they succeed at cracking technical challenges. Here, Dr. [...]

Announcement: Appointment of Drug Hunter Advisory Board Member: Andrew Setikas Drug Hunter is pleased to introduce a new member of our Advisory Board, Andrew Setikas. As Chief Business Officer at California Life Sciences, Andrew Setikas has been at the forefront of record growth for the organization, and during his tenure spearheaded efforts [...]

This high-level overview of 2021’s novel large molecule drug approvals is the 2 nd in a series of focus articles on 2021’s new drugs (see the small molecules here ). You can find our deep-dive on 2021's large molecule drug approvals here . There were: [...]

Announcement: Appointment of Drug Hunter Advisory Board Member: Gary Yeung, CFA Drug Hunter is pleased to introduce a new member of our Advisory Board, Gary Yeung . Gary Yeung is a life science executive (President, COO, CFO, and CBO), board member, advisor, and investor with extensive strategy, finance, business development, and operations [...]

We’ll be reviewing 2021’s novel FDA drug approvals in a series of articles, starting with this high-level overview of the small molecule drugs approved by the FDA in 2021. You can find Part 2 on First-in-Class Small Molecules here and the 2021 Large Molecules series here . Our deep dive on Small Molecule Oncology Approvals is also live [...]

Announcement: Appointment of Drug Hunter Advisory Board Member: Wendy Young, Ph. D . Drug Hunter is pleased to introduce a new member of our Advisory Board , Dr. Wendy Young. Wendy Young, Ph.D. is a seasoned drug hunter and biotechnology, pharma and life science executive with more than 25 years of experience in the discovery and development [...]

If you’re here reading about drug discovery for fun, you’re probably a drug hunter. You might be someone on your way to a leadership role in pharma or biotech. Maybe you’re decades into your career and already leading an R&D division. You don’t have a PhD in drug hunting, and it’s unlikely to be in your job description. But something makes [...]

We've just published the final set of Molecules of the Month for 2021, and now it's time to nominate your favorite molecules for 2021's Molecules of the Year! Nominees should have either been first disclosed in 2021 or had a major new update in 2021 (e.g. clinical trial readout, publication, business transaction, approval). The molecule must [...]

New drugs are discovered by teams, not individuals. "Drug discovery is a complex undertaking, and I enjoy the collaboration with many people from different disciplines and expertise areas that it takes to solve this impossible puzzle," says reviewer Joachim Rudolph . Drug Hunter also takes a community to build, and we [...]

Dear Drug Hunter, It's gotten harder and harder to keep up with everything that's going on in the industry. From new company launches to drug approvals, endless publications to regulatory updates, the volume of information drug discovery leaders need to make good decisions seems endless. Our mission is to save you time by curating industry [...]

In Aug. 2021, immuno-oncology company, Trillium Therapeutics, was acquired by Pfizer for $2.3 billion , adding Trillium’s two CD47-targeting biologics, TTI-621 and TTI-622, to Pfizer’s oncology pipeline. The acquisition followed Gilead’s $4.9B buyout of Forty Seven in early 2020, after clinical data was presented on Forty Seven’s lead, the [...]

Recently our non-profit partner, California Life Sciences , completed nominations for the 2021 Pantheon Award for Scientific Advancement . We’re glad to see several drug hunters and drug discovery companies across the award categories, and we hope you’ll help get some industry drug hunters deserved recognition for their achievements by voting [...]

The first disclosures of new drug candidates are always the highlight of medicinal chemistry conferences. Six novel drug candidates were recently disclosed by European companies at the European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (EFMC-ISMC) Conference in [...]

Recently, our team at Drug Hunter compiled the lead programs and mechanisms of small molecule and large molecule biotechs that IPO’d in 2020. We asked featured reviewers from our community what stood out to them about the science of this group of companies, and here are some highlights that emerged from the discussion. Any thoughts and [...]

Looking at the pipelines of recent biotech IPOs is a great way to get a snapshot of new technologies and approaches to drug discovery or to see what’s coming in smaller indications. Complementing our recent highlight of large molecule-focused companies, below is a summary of 2020’s class of biotech IPOs focused on small molecule drug [...]

We asked the global drug discovery community to vote on their favorite molecule from 2020, and the results are in. The community’s 2020 choice for Small Molecule of the Year is GS-6207 (lenacapavir), the awe-inspiring HIV capsid inhibitor published by Gilead Sciences in a 2020 issue of Nature.

Browsing through the pipelines of recent biotech IPOs is great way to catch up on emerging targets, novel drug modalities, and science at the edge of development. Unlike conferences and publications which tend to be a lagging indicator of what’s going on in industry (with many publications only being released years after a program has ceased [...]

While biologic drugs currently dominate in immunology by sales , small molecule immunomodulators (SMIMs) are making a comeback fueled by better understanding of intracellular signaling pathways and new hit finding technologies. SMIMs can be grouped into two categories: those that engage large molecule (LM) targets in a new [...]

Afternote: We're pleased to see Dan Erlanson made it as a finalist in the awards and Amgen's sotorasib won " Product of the Year ." Well deserved! Thanks to our readers for voting. Which drug hunters are making the greatest scientific contributions to drug discovery R&D? Our non-profit partner, California Life Sciences , is currently taking [...]

On Jun. 23 rd at 11AM PST, Dewakar Sangaraju and Dennis Hu gave a PBSS/CLSA webinar titled “Highlights from 2020’s FDA New Drug Approvals,” organized by Cyrus Khojasteh and Shichang Miao . One interesting fact about each approved small molecule drug was shared, along with statistics and specific case studies from the cohort of interest to the [...]

There was a hilarious set of memes circulating the internet on scientific papers thanks to xkcd.com’s original comic . Here’s our drug discovery scientist’s parody. Since people expressed an interest in being able to find this again, here it is: Explore drughunter.com for more on drug discovery.

There were 15 novel large molecule drugs approved in 2020, an increase over the 12 large molecule drugs approved in 2019 . Here’s a visual list of the FDA’s 2020 large molecule drug approvals , with more scientific details and references below. There is no significance to the order in which molecules are presented. This summary is intended [...]

On Feb. 16, 12:00PM PST, Dr. Mira Pochon, Staff Scientist and Head of Translational Biology at Global Blood Therapeutics, gave a PBSS/CLSA webinar on one of 2019's drug approvals , voxelotor (GBT440).  Mira has been with GBT since it’s early days in 2011.  GBT’s chemistry team was led by their CSO Dr. Brian Metcalf, former head of drug [...]

Assume a cow is an evenly distributed sphere... sometimes. I happened to take an animal physiology course in college because my girlfriend (now wife) needed it for her biology major and taking a class together about bird metabolism was my idea of a nice date.  I had no idea it would end up being one of the most useful courses in my career [...]

Learning from industry leaders is one of the best ways to grow as a drug discovery professional. This table lists some of the top drug discovery blogs and biopharma social media influencers, all of whom are clearly passionate about their work. These are excellent, free resources that offer valuable insights and perspectives.

It's hard not to think about infectious diseases at the moment, but it's a great time to review the drug discovery literature. One area of drug discovery that has deep roots in infectious disease research is targeted covalent inhibition. Targeted covalent inhibitors form covalent bonds with discrete targets (as opposed to [...]

Of the 2019 biotech IPOs on the major US exchanges, there were 24 companies focused on developing non-small molecule drugs, about the same number as those developing small molecule drugs . Here’s a list of the companies (by market cap at IPO) along with a short summary of the key concepts for each company's main programs. *International [...]

At the time of this writing Kim Huard was one of Genentech’s Senior Scientists, and has spent a decade looking for new medicines.  She spent eight years at Pfizer at the Groton and Cambridge sites before joining us in California. She's currently a Director in the Discovery Chemistry department leading teams of scientists in pursuit of new [...]

Of the 2019 biotech IPOs on the major US exchanges, 25 companies are focused on discovering and developing small molecule drugs. Here's a list of the companies (by market cap at IPO, top to bottom) along with the main mechanisms of action of the lead molecules and other publicly disclosed targets. The largest company by market cap. at the [...]

This article introduces the Topliss tree and Topliss schemes for analog synthesis, illustrates when they might be useful, and provides easy-to-use posters or "cheat sheets" of the original schemes. By Christian Kuttruff Why are the Topliss Tree and Topliss Schemes Useful? Imagine you’re on a new project that has just conducted a chemical [...]

This post briefly introduces chimeric molecules and companies working on them, contains a list of 10 recent “hot” papers in this field, and some predictions for where chimeras might head. It’s Chinese New Year time, which means a significant part of the global biopharma supply chain has ground to a halt, due to our colleagues and suppliers in [...]

or, How I Learned to Stop Worrying and Love My Own Definition. Recently I posted on “biologic drugs” which were approved in 2019 . All was well in my little scientific universe, until I received this in an email: “You recently reported "14 novel biologic drugs," referring to 'novel' biopharmaceuticals approved CDER. But, … You also include [...]

This article explains what LogD is, why LogD (or LogP) is important in drug discovery, rookie mistakes in drug discovery that come from overlooking LogD or LogP, and contains a LogD reference poster that shows the estimated amount of potency attributable to lipophilicity considerations alone. By Dennis Hu Jump to Cheat Sheet Lipophilicity is [...]

2019 was another big year for novel drug approvals (48 in total) though it wasn't the record year of 2018 (with 59). The overall explosion in biologic drugs / non-small molecule modalities continued with year with 14 novel biologic drugs, including 3 monoclonal antibodies, a recombinant fusion protein (Reblozyl), 3 ADCs, an siRNA drug [...]

2019 was another big year for drug discovery, with 29 FDA novel drug approvals for small molecules (including istradefylline which was first approved in Japan, but not including brilliant blue G, fluorodopa F18, Ga-68-DOTATOC, bremelanotide, afamelanotide, and ferric maltol, which could all be considered small molecules by some definitions) [...]

We all knew process scientists were good, but the Merck and Codexis teams just took it to another level!  Unnatural nucleosides like Merck’s reverse transcriptase inhibitor islatravir ( 1 , Figure 1) are well-known to be challenging to synthesize by traditional methods, as evidenced by several published chemical syntheses [...]

This table features a selection of some of the best drug discovery journals. While not exhaustive (our team’s RSS feed includes hundreds), this is a subjective list of where to find the most valuable articles for those entering the field.

This table features a selection of some of the best books on drug discovery, as well as related topics such as pharmacology, toxicology, pharmaceutics, and biotech. While nothing can replace hands-on industry experience, a few books serve as valuable references and offer insights into the realities of drug discovery. We recommend this list as a useful technical resource or as an informative introduction to the broader field of drug discovery, beyond any single discipline.

This table contains a list of some of the best drug discovery websites, online databases, and other online resources for drug hunters everywhere. If you have a suggestion for websites that we may have missed, let us know!

You’ve probably lived this story before: you’re working on your favorite kinase, YFK1, and are looking for selective inhibitors over YFK2.  The problem is, they’re virtually identical near the active site, save for a single residue sitting in the back pocket that your amazing structural biologist has identified.  The team [...]

Having a clinical drug-induced liver injury (DILI) signal is a surefire way to kill a drug candidate in non-serious indications like pain or chronic indications like diabetes, and will even give oncologists second thoughts as cancer patients are living longer. What can we do to prevent it? Plan A: Small Pill and No Greaseb ombs A widely [...]

Protein-ligand interactions are driven predominantly by strong hydrogen-bonding interactions, de-solvation energetics, and other entropic considerations including ligand lipophilicity. However, the combination of many weaker interactions can contribute to potency, and are often necessary to obtain selectivity when targets and anti-targets [...]

The C-H --- O hydrogen bond is so well established in structural biology today, that it's been overlooked that the C-H --- O hydrogen bond was first proposed by a woman, June Sutor, in a 1960's Nature article.[1] Hydrogen bonds were then assumed to be linear (A-H···A’ between 150-180º), and the C-H --- O hydrogen bonds proposed by Sutor are [...]

With the biochemistry magic available to the liver, it's a wonder that anything we consume is well-tolerated. Even carboxylic acids are structural alerts as they can be converted to bioreactive acyl glucoronides. The best we can do as drug hunters is minimize the risk of toxic metabolite formation and apply assays appropriately to select [...]

There are catalysis geniuses (looking at you, process chemists!) and then there are those of us just looking to put compounds in vials.  Here are the simplest conditions that'll get you what you want 90% of the time.  Beyond that you'll need to ask a guru like Nick White or Malcolm Huestis. Hope this table helps. Explore drughunter.co m for more.

The global cancer immunotherapy pipeline continues to explode with nearly double the number of active targets in 2019 vs. only two years ago, comprising 3,876(!!) active drugs, with a subset undergoing >5000 active clinical trials. In 2016, I listened to Dan Chen, former Global Head of Cancer Immunotherapy Development at Genentech, comment on [...]

Scientists from GlaxoSmithKline’s Stevenage site have an excellent article in J. Med. Chem. showing that cyclopropyl pyran (CPP) groups can serve as viable isosteres to N-pyrimidyl morpholines thanks in part to favorable cyclopropane σ -> aryl π interactions. N -aryl morpholines are privileged motifs in drug discovery, and suitable [...]

This article contains a pharmacokinetics reference table ("PK cheat sheet") with common cross-species physiological parameters relevant to PK, including animal size, liver blood flow, kidney blood flow, and body volumes. When interpreting compound pharmacokinetic (PK) data, it's helpful to have reference values to compare experimental data to [...]

Of the record 59 FDA drug approvals from 2018, the majority were small molecules (64%). Keep at it, chemists! :) Oncology and infectious diseases were the areas with most small molecule approvals, followed by genetic/rare diseases. Some more statistics below. Last year the FDA approved a record 59 novel drugs , which included 38 small [...]

Modern hit-finding technologies are incredible. Dean Brown and Jonas Bostrom at AstraZeneca have a very nice review out summarizing the hit-finding strategies for 66 clinical candidates published from 2016-2017. Some highlights include a clinical candidate from DNA-encoded libraries at GSK, the discovery of an RNA-binding drug candidate by [...]

BMS-986142 is a reversible BTK inhibitor with two axial stereocenters.  BMS synthetic chemists were able to make >200 kilos of this compound as a single isomer using this route.  Wow. Atropisomers are a nightmare in drug discovery.  Axial stereocenters are not easy to set predictably, separation of isomers is a pain, and the products are hard [...]

Checkpoint inhibitors like pembrolizumab (Keytruda) have revolutionized treatment for many late-stage cancer patients, including Jimmy Carter. Recently, Keytruda stunned the world again with efficacy in metastatic non-small cell lung cancer, the leading cancer killer. Here's a summary of its recent successes and the surprising path Keytruda [...]

Knochel's group has shown that you can fluorinate Grignard reagents without decomposition via single-electron transfer reactivity (SET) by a simple solvent switch from THF to DCM. A common way to prepare aryl fluorides is through lithium-halogen exchange, followed by trapping with N-fluorosulfonimide (NFSI).  This isn't always viable, as the [...]

Gleevec (imatinib) was the first tyrosine kinase inhibitor approved for the treatment of cancer and one of the first products to emerge from "rational drug design."  It's invention changed chronic myeloid leukemia from an incurable death sentence to a manageable disease. Here's a look back on the tremendous value it's created over the last [...]