Despite the remarkable emergence of HAART in the 1990s, the fight against HIV infection is by no means finished. At the ACS Fall 2024 meeting in Denver, CO, Gilead Sciences presented the structure and discovery story of elunonavir (GS-1156), a novel HIV protease inhibitor with remarkable metabolic stability and a human half-life exceeding two weeks. Based on BMS’ atazanavir, the compound incorporates structural elements inspired by Gilead’s HCV NS5A inhibitor program which led to ledipasvir, as “stabilizer” motifs to avoid the extensive CYP metabolism seen in current inhibitors.

September’s Molecules of the Month include Genentech’s HPK1 inhibitor for cancer immunotherapy and Novo Nordisk’s CB1 receptor inverse agonist for metabolic disorders. We also feature TAK-861, Takeda’s highly selective OX2R agonist, which has entered a pivotal Ph. III trial. Other notable molecules from September include a small molecule IL-17 inhibitor from Novartis and Boehringer Ingelheim’s pan-KRAS heterobifunctional degrader. You can read more about the compounds that made our September 2024 Molecules of the Month list and check out recent articles for each, linked below: GNE-6893 – An or...

BMS-986408 is an oral, dual DGK ⍺ and ζ inhibitor currently in a Ph. I/II trial in patients with solid tumors. The compound was identified stemming from a phenotypic screening approach, and subsequent target deconvolution revealed DGK to be the target. If approved, it would be a first-in-class intracellular checkpoint inhibitor of DGK. This is an excellent case study on how to overcome a DILI risk associated with BSEP inhibition, as well as how to improve solubility and PK properties of your compounds through the introduction of polarity, reduction of aromatic rings, and increase in f(sp3).

STX-478 is a wild-type-sparing, oral, CNS-penetrant, novel allosteric inhibitor of mutant PI3Kα (phosphatidylinositol-3 kinase α) 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.

Arvinas’ ARV-471 is an orally bioavailable CRBN-based ER PROTAC degrader for treating patients with ER+/HER2-breast cancer and the first PROTAC to enter Ph. III clinical trials. This molecule one-pager serves as a reference guide, offering an overview of the scientific significance of Arvinas’ ARV-471 program. It includes links to key presentations, publications, patents, preclinical and clinical PK data summaries, and more.

Inavolisib is a PI3Kα isoform-selective kinase inhibitor and monovalent degrader of the mutant p110α catalytic subunit of mutant PI3Kα. The molecule selectively depletes mutant p110α in cancer cells with active RTK (receptor tyrosine kinase) signaling and is in several ongoing or planned Ph. III trials for breast cancer. In October 2024, it received FDA approval for use in combination with palbociclib and fulvestrant to treat adults with endocrine-resistant, PIK3CA-mutated, HR+/HER2- breast cancer. This article explains how it works, how it was discovered, and why it matters.

This summary of September's major clinical updates features FDA approvals, drug withdrawals, anticipated regulatory decisions, notable trial results, new NDA submissions, clinical trial setbacks, and the initiation of new clinical trials.

In this article, you'll find a curated selection of >70 molecules from August that piqued our interest, highlights of some of our favorites, and explanations of why they're worth watching.

This article highlights the key drug discovery patents published in August 2024, including AKR1C3-dependent KARS (not KRAS!) inhibitors for NRF2/KEAP1-mutated cancers and DHX9 helicase inhibitors of MSI-high tumors. It also covers the development of MK2 degraders for inflammatory diseases and small molecule IL-17A inhibitors that show promise in modulating inflammation. Additionally, we cover Roche’s take on Revolution Medicines’ macrocyclic pan-KRAS inhibitors, which show improved PK profiles, and novel non-hydroxamate LpxC inhibitors for treating Gram-negative bacterial infections.

As part of our Flash Talk webinar series, we present a PDF of Nicholas Meanwell's slide deck entitled "The Chemist's Playbook: Impactful Bioisosteres for Modern Drug Design". Check out the recording of the talk on our Drug Hunter YouTube channel.

KEAP1 inhibition/NRF2 activation has been hotly pursued in recent years for immunology indications; however, in oncology, NRF2 degradation has been posited as a novel therapeutic mechanism for specific cancers. Vividion has already disclosed work on covalent KEAP1 inhibitors, but at the recent ACS Fall 2024 meeting, the structure and discovery story of their clinical oral covalent activator of KEAP1 were disclosed, identified through careful analysis of the data from their inhibitor screen.

NDI-101150 is an oral HPK1 inhibitor discovered by Nimbus Therapeutics and is currently in Ph. I/II clinical trial in advanced solid tumors. HPK1 is a compelling immuno-oncology target due to its critical role in regulating T-cells, B-cells, and dendritic cell-mediated immune responses. HPK1-deficient mice demonstrate enhanced anti-tumor T-cell responses and resistance to tumor growth. In this article, we detail the discovery of NDI-101150, as highlighted by Nimbus at the ACS Fall 2024 First-Time Disclosures session, interim results from the clinic, and more.

As part of our Coffee Chat webinar series, our team (Lew Pennington, Matt Hesse, and Dennis Koester), explored Drug Hunter’s patent highlight feature and shared their favorite molecules and notable stories from recent patent filings. we present a PDF of the slide deck. Check out the recording of the talk on our Drug Hunter YouTube channel.

We know keeping up with the latest developments in drug discovery can be a challenge, so we’ve simplified the process for you. We’ve reviewed thousands of newly published patent documents to bring you a curated list of over 200 key patents released in August 2024. Each entry comes with detailed commentary to help you navigate the content quickly and efficiently.

Arvinas’ ARV-393 is an orally bioavailable PROTAC that degrades BCL6 via CRBN-mediated ubiquitination and proteasomal degradation intended for the treatment of NHL. At the AACR San Diego 2024 meeting, Arvinas disclosed the structure and discovery story of this molecule, which exhibits first-in-class potential. This article covers the key SAR observations that led to the invention of this orally bioavailable PROTAC®, its performance in a triple-hit, high-grade BCL and R-CHOP-resistant cell line, and why sustaining BCL6 knockdown beyond 24 hours was critical for the success of this program.

BridgeBio’s BBO-8520 is a selective, covalent KRAS(G12C) inhibitor which differentiates itself from the pack by engaging the (ON) state of the protein, potentially conferring increased clinical benefit in KRAS(G12C)-driven cancers, including overcoming resistance to current treatments. Disclosed at the 2024 AACR Annual Meeting in San Diego, is currently in a Ph. I trial in patients with advanced non-small-cell lung cancer. This article covers the structure, mechanism of action and preclinical efficacy that marks this compound out as one to watch.

During Drug Hunter’s Flash Talks, experts talk in-depth about hot topics in drug discovery. These experts also share insights beyond the subjects of their presentations, such as how they got inspired to become a drug hunter, what their favorite molecule is, what excites them most in drug discovery today, and what advice they wish they could give their younger selves. Here is a quick look at some of these insightful nuggets from Flash Talks hosted between January and August 2024.

PLX-4545 is an oral CRBN-based molecular glue degrader of IKZF2 in Ph. I trials. It potentially addresses anti-tumor immunity suppression within the TME, critical in checkpoint blocker resistance. Tumors use IKZF2 to regulate the function of regulatory T cells and inhibit effector T cells. IKZF2 depletion in regulatory T cells enhances the anti-tumor response. The discovery and structural data of PLX-4545 were presented by Kevin Freeman-Cook at the ACS Fall 2024 First-Time Disclosures session in Denver, CO. We are reporting the discovery story and its potential impact on immuno-oncology.