Shaima Qunies

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!

To help you quickly scan the patent literature, we’ve distilled down thousands of new documents into a searchable table of over 200 selected patents focused on key areas in drug discovery, all published in May 2024. This resource is enriched with detailed highlights on selected molecules targeting high-interest areas such as STING antagonists, WIZ degraders, RNA degraders, and macrocyclic amine-based OX2R modulators.

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!

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!

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.

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!

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.

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.

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

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.

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

Nrf2/KEAP1 modulation has been pursued since the discovery that dimethyl fumarate and its metabolite protect CNS neurons via up-regulation of Nrf2-depdendent activities. Compounds with greater selectivity have been sought for many years, culminating with the approval of the KEAP1 inhibitor, omaveloxolone. Vividion disclosed their efforts to identify the covalent KEAP1 inhibitor, VVD-702. This ACS Spring 2024 disclosure is an excellent case study for covalent hit finding using chemoproteomics, covalent compound optimization, and the use of an uncommon but surprisingly stable covalent warhead.

From WRN helicase to KRAS G12V, there were numerous hot targets of interest with patent applications published in January 2024. Here, we curated a searchable table comprising key information for more than 200 patents from January 2024 of potential interest to drug hunters, along with highlights from some of our favorites, including several degraders and molecules targeting Nrf2, KRAS G12V, MAGL, WRN, among others.

NaV1.8, a member of the voltage-gated sodium channel (NaV) family, is predominantly expressed in peripheral sensory neurons. Based on rodent NaV1.8 knockout and knockdown studies and a 2012 report of gain-of-function mutations in humans, NaV1.8 has been linked to nociceptive, inflammatory, and neuropathic pain, including chronic neuropathic pain. This compound roundup provides a historical recap of both preclinical and clinical NaV1.8 inhibitors that shaped the landscape for the new era of pain management we are witnessing today.

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.

PF-07817883 (ibuzatrelvir) is an oral, second-generation SARS-CoV-2 M^pro inhibitor developed by Pfizer. These efforts follow the success of Pfizer's antiviral combination drug, Paxlovid, which was granted Emergency Use Authorization by the FDA for the treatment of COVID-19. PF-07817883 was granted Fast Track designation and recently completed a Ph. II clinical trial in outpatient adults with COVID-19 symptoms. This article details the discovery strategy for PF-07817883, which includes addressing metabolic soft spots identified through MetID studies, recent clinical developments, and more.

Olutasidenib, discovered by Forma Therapeutics and marketed by Rigel, is an oral, brain-penetrant, selective mIDH1 inhibitor. It was granted Orphan Drug Designation and approved in December 2022 by the FDA for adults with relapsed/refractory acute myeloid leukemia. Approval was granted based on a Ph. I/II trial showing a 35% CR+CRh rate and a favorable 25.9-month median duration. This article describes the discovery and development of olutasidenib, how it is distinct from other mIDH inhibitors, and its potential in treating gliomas.

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.

STC15 is Storm Therapeutics' first-in-class and first-to-clinic inhibitor of the post-transcriptional RNA modifier, METTL3, which progressed from HTS hit to clinical development in less than three years. METTL3 inhibitors have been previously identified, but no METTL3 inhibitors have entered clinical development until now. In this article, we explore METL3 as a therapeutic target, highlight the discovery story of STC15, its fascinating mechanism of action, provide the latest clinical development update, and much more.

While KRAS(G12C) has been the most readily targeted form of KRAS thanks to its reactive cysteine residue, other mutations such as KRAS(G12D) make up the majority of KRAS-mutated cancers. In this roundup, we highlight 12 inhibitors, degraders, and other molecules that reflect progress in overcoming this challenge, including some of the first clinical candidates targeting non-KRAS(G12C)-mutant tumors, and why these molecules are notable.

RLY-2608 is an oral, mutant-selective PI3Kα allosteric inhibitor by Relay Therapeutics. Current FDA-approved PI3Kα modulator (alpelisib) and a clinically advanced molecule (inavolisib) are limited by their off-target toxicities associated with the inhibition of WT PI3Kα, leading to hyperglycemia and rash. RLY-2608 is currently in a Ph. I as a single agent and in combination with fulvestrant for HR+/HER2- breast cancer treatment. This article reviews the discovery of RLY-2608, its mechanism of mutant selectivity, how it compares to other molecules, recent clinical developments, and more.

NT-0796 is NodThera's pro-drug inhibitor of the NLRP3 inflammasome. NT-0796 is currently in a Ph. Ib/IIa trial in obese individuals at risk of developing atherosclerotic cardiovascular diseases. NT-0796 has the potential to reduce neuroinflammation in Parkinson’s disease. The NLRP3 inflammasome has emerged as a hot target due to its connection to Alzheimer’s disease, Parkinson’s disease, gout, and other diseases. Here is a detailed review of the role of NLRP3 inhibition in treating atherosclerosis, how NT-0796 was identified and what makes it special, clinical development, and more.

Nuvalent’s lead compound, NVL-520, is an oral, brain-penetrant, TRK-sparing, and potential best-in-class ROS1 kinase inhibitor that recently entered Ph. II of the ARROS-1 trial (NCT05118789) in patients with advanced ROS1-positive NSCLC. This article highlights what makes the Nuvalent’s NVL-520 program scientifically notable, including what gives it a potential best-in-class profile as a ROS1 inhibitor, the emerging toxicology of hard-to-avoid off-targets, an interesting synthetic route to the small macrocycle, and more.

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant phosphatidylinositol-3 kinase α (PI3Kα), targeting a cryptic pocket near the ATP-binding site. PI3Kα plays a central role in many cancers, and has been recently highlighted in coverage of 2021 Molecule of the Year nominee and PI3Kα degrader inavolisib. Currently approved PI3Kα modulators are limited by their off-target activities on WT PI3Kα and other kinases, leading to significant side effects including hyperglycemia and rash.

Jecure’s JT001 is a selective inhibitor of NLRP3 inflammasome and among the earlier compounds in this now highly competitive space. In 2018, Genentech bought Jecure Therapeutics for an undisclosed amount, gaining access to Jecure’s NLRP3 inhibitor JT001. While there are many other NLRP3 inhibitors now in the space, JT001 is an interesting example of an initial attempt to overcome liver toxicity with well-known NLRP3 inhibitor MCC950. However, the molecule ran into its own kidney toxicity issues, making this an intriguing toxicology case study.

Atrasentan (ABT-627/A-127722) is an ETA receptor antagonist that was originally discovered by Abbott (AbbVie) in the 1990s to treat prostate cancer. Unfortunately, clinical data with the compound in prostate cancer was insufficient for approval, and AbbVie pivoted the compound to chronic kidney diseases instead, ultimately conducting a large, 5,000+ patient trial (SONAR) that was published in 2019.

Vorasidenib (AG-881) is a brain-penetrant allosteric inhibitor of mutant isocitrate dehydrogenases 1 and 2 (mIDH1/2) from Agios and Celgene that made headlines summer 2023 due to its stunning efficacy for treatment of glioma in patients with mIDH1/2.

This Featured Case Study reviews how it was discovered, how it works, and why it matters.

Orforglipron is an oral non-peptide glucagon-like peptide-1 (GLP-1) receptor partial agonist that entered Ph. III for obesity and type-2-diabetes mellitus (T2DM). This 2020 and 2023 Molecule of the Year nominee (nominated initially back when it was still in Ph. I) was first discovered by Chugai Pharmaceuticals under the name OWL833, then licensed by Eli Lilly for worldwide development under the name LY3502970. The article discusses where it sits in the GLP-1R agonist landscape, why it’s scientifically notable, how it works with illustrations from cryo-EM structures, its synthesis, and more.

Vadadustat (Vafseo) from Akebia Therapeutics is an oral hypoxia-inducible factor prolyl-4-hydroxylase domain (HIF-PHD) inhibitor developed for anemia in patients with chronic kidney disease (CKD). It received FDA approval on March 27th, 2024 for patients on dialysis for at least three months, after regulatory challenges including an earlier complete response letter due to safety concerns. This makes vadadustat the second FDA-approved HIF-PHD inhibitor for the treatment of anemia in CKD for dialysis-dependent patients after GSK’s daprodustat’s approval in Feb. 2023.