Matt Hesse

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 4-part series we bring you the biologics-focused deals 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. 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.

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.

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

As part of our "Molecules of the Month" and "Molecule Roundup" series of articles, which bring you the most interesting drug discovery molecules published each month, by member request, we have brought together recently highlighted molecules into a single searchable table. This tool allows you to see longer term-industry trends in therapeutic areas, target selection and chemical matter to inspire ideas for your drug discovery pipeline.

As part of our series of monthly patent roundup articles, which bring you highlights of the most relevant drug discovery IP disclosures, by member request we have collated recent selections into a single searchable table. This tool allows you to see longer-term industry trends in therapeutic areas and target selection to inspire ideas for your pipeline.

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.

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.

PRMT5 is an epigenetic “synthetic lethality” target that has attracted much attention among drug hunters. The first generation of PRMT5 inhibitors was limited by systemic toxicities resulting in a cooling of industry interest, until the recent identification of tumor-specific inhibitors. These second-generation compounds target the MTA:PRMT5 complex in MTAP-deleted cancers—15% of all tumors—leading to a revival of the target. Read on to find out which companies are prevailing in the search for a first-in-class PRMT5 inhibitor and how their clinical compounds differentiate.

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.

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.

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.

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.

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.

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.

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.

Inaxaplin (VX-147), developed by Vertex, is an inhibitor of APOL1 channel activity currently in a Ph. II/III pivotal study for the treatment of chronic kidney disease caused by specific variants of the APOL1 gene. It was recently granted Breakthrough Therapy designation by the FDA and PRIME designation by the EMA. The discovery story, which is an excellent case study for the use of MetID. Inaxaplin has been called “the most important genomic-driven drug discovery for chronic kidney disease this century”, acting on a target with a fascinating human genetic validation story.

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.