Lew Pennington

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.

LTGO-33 is a state-independent NaV1.8 inhibitor with over 600-fold selectivity for the NaV1.8 channel over other sodium channels. Chronic pain affects millions, and existing treatments offer limited efficacy, risk of abuse, and low tolerability. There is an urgent need for new drugs that target validated pain mechanisms such as NaV1.8, which has recently gained increased attention. This article explores the unique pharmacological properties of LTGO-33, setting it apart from earlier NaV1.8 inhibitors.

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. Following our open-access industry overview, in the final installment of this four-part series we bring you the biologics-focused deals opening checkbooks in 2023.

Novartis’ HRO761 is an oral allosteric WRN helicase inhibitor, aimed at treating MSI-high and dMMR tumors. This article details the discovery of HRO761 and highlights the importance of selecting appropriate assays during early HTS as well as transferable medicinal chemistry strategies to optimize permeability and solubility through the modulation of LipE, neutral TPSA, chameleonicity, and non-classical zwitterions. It also explores the X-ray structure of HRO761 bound to WRN, how it differentiates from Vividion's VVD-214, its preclinical activity, clinical status, chemical synthesis, and more!

In June, we saw several FDA approvals for treatments targeting primary biliary cholangitis and COPD. The industry witnessed multibillion- and multimillion-dollar deals across various therapeutic areas. Advances were made in obesity therapeutics, with novel targets and clinical readouts for GLP-1 agonists and NLRP3 inhibitors. Alkermes and Takeda reported results for OX2R agonists in narcolepsy, while an antimalarial drug showed promise in PCOS. Despite these advancements, there were clinical trial failures for key molecules. Here's a recap of the most notable news highlights from June 2024!

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 part 3 of this 4-part series, we bring you the top-ranked small molecule-focused deals by value. Covering a range of targets and modalities, this article gives Drug Hunter members in-depth background and analysis of the hottest science opening checkbooks in 2023.

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. Following our open-access industry overview, in part 2 of this 4-part series we bring you the small molecule-focused deals, ranked 11-20 by value. Covering a range of targets and modalities, this article gives Drug Hunter members in-depth background and analysis of the hottest science opening checkbooks in 2023.

To select May’s Molecules of the Month, our team evaluated hundreds of molecules from thousands of papers, press releases, conference presentations, and other materials. Check out our curated roundup of more than 60 additional molecules below that caught our interest from May, including highlights of some of our favorites, and perspectives on why these are molecules to watch.

ORIC-944 is a second-generation, orally bioavailable PRC2 inhibitor, targeting the allosteric EED subunit. EZH2 inhibitors typically require frequent dosing due to poor drug-like properties. This article describes the previously undisclosed structure-based design of ORIC-944 into a potential best-in-class PRC2 inhibitor with enhanced solubility, metabolic stability, and prolonged clinical half-life compared to EZH2 inhibitors. It also highlights ORIC-944's capability to reprogram refractory, AR-independent prostate tumors to an AR-dependent state, the synthesis, clinical data, and more!

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.

Pfizer’s oral, CDK4-selective inhibitor PF-07220060 has the potential to revolutionize treatment of HR+/HER2- breast cancer through avoiding the neutropenia DLTs associated with SoC CDK4/6 drugs and permitting greater coverage of the desired CDK4 target. Our full article outlines data presented at AACR 2024, covering the molecule’s course from in silico-informed screen, through structurally enabled optimization against CDK6 and GSK-3β to promising preclinical profile. Fresh clinical data showed efficacy and tolerability supporting PF-07220060's clinical progression.

In May 2024, several significant transactions worth millions and billions of dollars took place to advance next-generation neuroplastogens, KRAS G12C inhibitors, Pompe disease treatments, and molecular glues. We also highlight positive clinical readouts for hot targets such as tetrameric transthyretin (TTR) stabilizers, Hedgehog pathway inhibitors, plasma kallikrein inhibitors, dipeptidyl peptidase 1 (DPP-1) inhibitors, and PCSK9 inhibitors. Here's a recap of the most notable news highlights from May 2024!

Cerevance’s CVN293 is an oral, CNS-penetrant, selective inhibitor of potassium efflux-mediated NLRP3-inflammasome activation in microglia for the treatment of neurodegenerative disorders. Cerevance’s NETSseq platform was used to discover a microglia-specific potassium efflux channel, KCNK13, which allows modulation of the NLRP3-inflammasome in the CNS without affecting peripheral innate immunity. Read the full article to discover highlights on the CNS-penetration of highly polar compounds and how particle size can be key to oral bioavailability

To select April’s Molecules of the Month, our team evaluated hundreds of molecules from thousands of papers, press releases, conference presentations, and other materials. Here we’ve curated a roundup of more than 60 additional molecules that caught our interest from April, along with highlights we found most notable.

In April 2024, patent disclosures continued to highlight the swift progress in targeting key therapeutic areas. The Drug Hunter team has carefully compiled a searchable database containing over 200 patents relevant to drug discovery. This resource is enhanced with detailed annotations and highlights some of the most promising molecules and targets, such as GPR84 antagonists, brain-penetrant TYK2 inhibitors, and tricyclic urea JAK2 V617F inhibitors, among others. This compilation serves as a valuable tool for drug hunters to stay abreast of the latest trends in drug discovery.

In the aftermath of the thalidomide tragedy, the FDA advised excluding females in the childbearing age from early-stage clinical trials. However, this policy resulted in the prolonged underrepresentation of women in clinical research, limiting knowledge about how drugs affect genders differently. Recent policy changes, including the NIH's emphasis on considering sex as a biological variable, aim to reduce these disparities by promoting more diverse clinical trial participation. This article explores the current landscape of endometriosis therapies and how it relates to women’s healthcare.

TNG348 is a synthetic lethal inhibitor of USP1 by Tango Therapeutics. Inhibiting USP1 disrupts DNA repair and replication mechanisms leading to the selective death of BRCA1/2-mutant cancer cells. Despite the clinical benefit of PARPi in treating BRCA-mutated or HRD+ tumors, some patients exhibit an inadequate response or develop resistance. USP1 inhibitors may hold promise in meeting this unmet clinical demand. This case study highlights USP1 as a synthetic lethal target, the current competitive landscape, how the Tango team overcame high microsomal clearance and hERG liabilities, and more.

There has been substantial interest in the development of screening methods capable of surveying a wider sample of chemical space and larger numbers of compounds. Over the past two decades, DEL technology has evolved into a broadly utilized and validated platform in drug discovery, yielding diverse hits for a wide range of biologically relevant targets. Read the full review for a historical and technical overview of DEL technology, including how libraries are prepared and screened, a comparison to other HTS methods, and examples of successful applications in drug discovery.

AstraZeneca has joined the race to gain approval for a first-in-class, orally bioavailable selective inhibitor of CDK2 with AZD8421, which was recently disclosed at the AACR San Diego 2024 “New Drugs on the Horizon” series. CDK2-selective inhibitors are a hot area right now, with their promise to overcome the resistance against approved CDK4/6 inhibitors. Read the full case study to learn about the CDK2-selective competitive landscape, the structural and kinetic data which underpin AZD8421’s CDK-selectivity and the preclinical activity data which has propelled it into the clinic.

BLU-222 is a potential first-in-class, orally bioavailable selective inhibitor of CDK2 discovered and currently in development by Blueprint Medicines for the treatment of advanced solid tumors. Read the full case study to learn about the competitive landscape of CDK inhibitors, the discovery story enabled by the DiscoveRx KINOMEscan screening platform, how exquisite kinome selectivity can be achieved despite ~100% active site sequence similarity between CDK1/2, how this molecule can potentially treat CCNE1-amplified and CDK4/6i-resistant tumor models, interim clinical data, and more.

In April 2024, there were promising examples of drug repurposing, significant clinical and regulatory milestones for therapies aimed at rare and pediatric diseases, the initiation of a rolling NDA submission for suzetrigine, substantial billion-dollar acquisitions, and positive trial results were reported for both a D1/D5 receptor agonist and a PARP1 inhibitor. However, the industry also had setbacks as demonstrated by the failed clinical trials for an MNK inhibitor and an NMDA receptor modulator. In case you missed anything, here’s a recap of the most notable news highlights from April 2024!

Zuranolone (ZURZUVAE™) is an oral positive allosteric modulator of CNS GABA signaling developed by Sage Therapeutics, in collaboration with Biogen, which was approved in August 2023 by the FDA for the treatment of postpartum depression (PPD). In 2019 Sage had received approval for brexanolone (ZULRESSO™), an IV formulation of the endogenous GABA PAM neurosteroid hormone for PPD, but an oral drug is expected to greatly increase access to treatment. Zuranolone was also investigated for major depressive disorder, although the FDA declined to extend approval for this indication.

SGR-1505, the first in-house clinical compound developed at Schrödinger, is an oral, allosteric MALT1 inhibitor currently in the clinic for the treatment of mature B cell malignancies. The discovery effort, disclosed at the ACS Spring 2024 meeting, was completed in an impressive 10 months, starting from a published scaffold. SGR-1505 demonstrated preclinical single-agent and combination activity as well as inducing resensitization in BTK and BCL-2 inhibitor-resistant tumors. The compound is currently progressing in a Ph. I trial in patients with mature B cell malignancies.

Throughout each month, the Drug Hunter team evaluates hundreds of molecules found in thousands of papers, press releases, conference presentations, and other materials to pick contenders for Molecules of the Month. Here, we curated a roundup of nearly 70 additional molecules that caught our interest from March 2024, including highlights from some of our favorites.

In March 2024, the landscape of patent disclosures continued to reflect the rapid pace of advances against key therapeutic targets. The Drug Hunter team has curated a searchable database encompassing over 200 patents pertinent to the field of drug discovery. This resource is further enriched with insightful spotlight on some of the most promising molecules and targets, including OX2R agonists, TEAD covalent inhibitors, NaV1.8 inhibitors, and selective PI3Kγ inhibitors, among others. This round-up provides a valuable tool for drug hunters to navigate the most recent trends in drug discovery.

Deciphera’s DCC-3116 is an oral ULK1/2 inhibitor targeting the autophagy pathway, a key mechanism of tumor survival and resistance to targeted therapy. Currently in two open-label Ph. I/II trials as a monotherapy and in combination with RTK pathway inhibitors, the structure and discovery of this first-in-class compound were recently presented at the ACS Spring 2024 meeting.

TNG462, developed by Tango Therapeutics, is a potential best-in-class, oral, protein arginine methyltransferase 5 (PRMT5) inhibitor currently in Ph. I/II clinical trial for MTAP-deleted solid tumors. TNG462 is designed to cooperatively bind to PRMT5 when complexed with its endogenous inhibitor methylthioadenosine (MTA), which accumulates in MTAP-deleted tumors. This triggers synthetic lethality in cells with an MTAP-deletion and spares healthy tissues with low MTA levels. A CNS-permeable analogue, TNG908, is also entering clinical trials for MTAP-deleted glioblastoma.

VVD-214/RO7589831 is an oral covalent, reversible, and allosteric inhibitor of WRN helicase discovered by the San Diego-based biotech Vividion Therapeutics and being developed by Roche for tumors marked by microsatellite instability and/or mismatch repair deficiency. Vividion has utilized its chemoproteomics platform to discover and develop novel treatment options for oncology targets. The structure and initial preclinical pharmacology data for VVD-214 were recently disclosed at the AACR Annual Meeting 2024 in San Diego. VVD-214 is currently being evaluated in a Ph. I trial.

The discovery that individuals with null mutations in the NaV1.7 exhibited pain insensitivity sparked interest in targeting NaV1.7 to potentially treat pain. Despite the potential of selectively inhibiting sodium channels like NaV1.7, NaV1.8, and NaV1.9 for pain management, developing selective inhibitors suitable for clinical use has proven challenging. This article complements our coverage of VX-548, NaV1.8 as a critical target in pain management, and our NaV1.8 compound roundup and provides a reminder of noteworthy preclinical and clinical NaV1.7 small molecule inhibitors as of April 2024.

ORIC-533, a potential best-in-class oral inhibitor of CD73 from ORIC Pharmaceuticals, is currently in a Ph. Ib trial for relapsed/refractory multiple myeloma (MM). It inhibits the CD73-mediated conversion of AMP to adenosine which generates an immunosuppressive tumor microenvironment and has the potential to be a next-generation immunotherapy. The in-depth use of X-ray structures led the team to discover a novel set of phosphonate bioisosteres which acheived bioavailability in a polar scaffold. The structure and discovery of ORIC-533 were recently disclosed at the ACS Spring 2024 Meeting.

Minipigs have recently gained prominence as an alternative non-rodent in vivo model for pharmacokinetic (PK), efficacy, and toxicology studies supporting human dose predictions. This article provides an overview of the use of minipigs in small molecule preclinical drug discovery research, tracing their historical background and outlining practical considerations for selecting them in studies focusing on hepatic metabolism, oral bioavailability, CNS penetration, and toxicology. It highlights minipigs' unique advantages and makes a compelling case for their continued use in preclinical research.

Companies inked notable high-profile transactions in March 2024, including AbbVie's purchase of Landos Biopharma for $137.5M, AstraZeneca's $2.4B acquisition of Fusion Pharmaceuticals, and its subsequent deal to buy Amolyt for up to $1.05B. The FDA approved the first treatment for MASH. In parallel, expectations are high for the approval of Xcovery's ALK inhibitor, ensartinib. Praxis made headlines with PRAX-628, a next-generation oral NaV modulator, which showed anti-seizure efficacy in a Ph. IIa trial. Read below for more details on these and other drug discovery news stories from March 2024

MK-1084 is an oral covalent inhibitor of KRAS(G12C) being developed by Merck (as part of a collaboration with Taiho and Astex), which is currently in a Ph. I trial (NCT05067283) for the treatment of solid tumors either as a monotherapy or in combination with their checkpoint inhibitor immunotherapy pembrolizumab (Keytruda™). The medicinal chemistry story was recently presented at the ACS Spring 2024 meeting in New Orleans, following a presentation of the Ph. I interim results by Merck at ESMO in Oct. 2023.

February 2024 saw numerous notable patent disclosures aimed at a variety of therapeutic targets across different disease areas. The Drug Hunter team has compiled a searchable table that includes more than 200 patents of relevance to the drug discovery industry. Accompanying the table are detailed notes, as well as standout features from some of our top picks, including MTA-cooperative PRMT5 inhibitors, heterobifunctional TYK2 degraders, strategies for engaging and reactivating mutant p53, and more.

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 February 2024 along with some highlights from some of our favorites below.

February 2024 was filled with notable scientific achievements and partnerships. Gilead and Novartis inked billion-dollar acquisitions, and Novo Nordisk and NeoMorph agreed to a $1.46B deal to discover molecular glue degraders. Additionally, Vertex introduced a promising new treatment for cystic fibrosis that is potentially superior to Trikafta. Takeda also made strides by advancing their OX2R agonist TAK-861, for treating narcolepsy type 1, into Ph. III clinical trials. Read this news roundup for more details on these and other drug discovery news stories that you may have missed from Feb 2024

Kymera's KT-474 is the first oral degrader to demonstrate activity in clinical trials outside cancer and Sanofi recently started a Ph. II trial with the molecule in AD, restoring life to IRAK4 as an immunology target. This article highlights why Kymera’s KT-474 program is scientifically notable, including how it differentiates from small molecule inhibitors, potential competitiveness with biologics, the first reported cryo-EM ternary complex of a heterobifunctional degrader, and why this 2023 Molecule of the Year Nominee will likely be considered a “landmark in drug discovery” for some time.

The accelerated approvals of Ras(OFF)-targeting KRAS G12C inhibitors sotorasib and adagrasib, decades in the making, marked the beginning of a new phase of KRAS drug discovery. While an increasing number of follow-on KRAS inhibitors are emerging with similar mechanisms of action, Revolution Medicines’ 2023 Molecule of the Year Nominee, RMC-6291, is representative of a completely novel approach that could become a strong addition to the clinical toolbox for KRAS, but also serves as proof-of-concept for a new class of small molecule therapeutics entirely.

M4205 (IDRX-42) is a highly selective type II receptor tyrosine kinase inhibitor of KIT, discovered by Merck KGaA and currently being developed by IDRx. The molecule is a notable example of kinase selectivity achieved with a non-classical hinge binder. M4205 (IDRX-42) has received an Orphan Drug designation and is currently being evaluated in a Ph. I/Ib FIH trial for GIST, one of the most common mesenchymal neoplasms in the GI tract.

Bexotegrast is a dual-selective αvβ6-αvβ1 integrin inhibitor with surprising efficacy and safety data from a Ph. II trial in idiopathic pulmonary fibrosis (IPF). The αv integrins have been studied for decades in indications such as cancer and IPF. Both small molecule and antibody-based integrin inhibitors have demonstrated preclinical toxicities in non-human primates. This article highlights the unmet need for effective therapies for IPF and related conditions, a comparison of bexotegrast with other integrin binders, and possible reasons why bexotegrast is different in terms of safety.