Drug Hunter

Drug Hunters in Denver! Another FANTASTIC evening with a fascinating group of stellar drug hunters in Denver! Got to hear stories from several hundreds years of collective drug discovery experience, including from one of the inventors of the first antibody-drug conjugate (ADC), pioneers of first-in-class molecules against KRAS and other targets, and more. Great to see folks from all over the world come in and hear their inspiring stories. Thank you for all who stayed out this evening Jennifer Allen, Bernhard Fasching, Julia Haas, Wendy Young, Denise Grünenfelder, Zhonghua Pei, Christa Müller, Philippe Mochirian, Anil Padyana, Claude Q., Michael Deligny, Jonathan Hempel, Jie Jack Li, Josh Haimson, Eric Newcomb, Magid Abou-Gharbia, and special thanks our team members Dennis Koester, Matthew Hesse, Shaima Qunies for co-hosting!

A Potent Intramolecular NLRP3 Glue Inhibitor Advancing Through Multiple Phase II Trials | https://lnkd.in/gafD96tz Novartis' NLRP3 inhibitor, NVP-DFV890, features a unique sulfonimidamide motif designed to reduce hydrolysis relative to traditional sulfonylureas. This potent compound, with promising PK in humans, is advancing through multiple clinical studies, including Ph. II trials for coronary heart disease and knee osteoarthritis. Presented by Angela Mackay at the EFMC-ISMC 2024 joint conference in Rome, this overview covers NVP-DFV890's discovery, as well as its preclinical PK and PD data. Read it on Drug Hunter | https://lnkd.in/gafD96tz

September 2024 Molecule Roundup | https://lnkd.in/g_T5p656 In this article, we present a curated selection of over 60 molecules from September that caught our attention, along with highlights of our top picks and insights into why they stand out. Article Link | https://lnkd.in/g_T5p656

Why Are VAV1 Degraders Such a Big Deal? Earlier this week, Novartis signed a deal for $150M upfront, up to $2.1B, with Monte Rosa Therapeutics. Drug Hunter scientists highlighted VAV1 patents earlier in the year and noted this program from a conference this summer (see link). Scientifically the program is notable as it suggests that CRBN E3-ligase-based degraders, which have traditionally been considered the most "drug-like" degrader category, can be applied to target proteins like VAV1 which do not have a canonical "G-loop" domain degron that CRBN recognizes. Expanding the scope of CRBN-based degraders has been of significant interest in the targeted protein degradation space and this clinical program suggests more is to come. Monte Rosa's VAV1 degraders appear to be exquisitely selective and orally efficacious in preclinical immunology models. The clinical development of VAV1 in healthy volunteers and immune-mediated disorders is notable given the high bar for safety in these areas, and the clinical history of imide-based degraders. Make sure your team has Drug Hunter access so you can catch these things well before they're published or seen in the news: https://lnkd.in/guVYGD9u

Managing Toxicities in a Unique NLRP3 Inflammasome Inhibitor Chemotype by AstraZeneca | https://lnkd.in/gKNb7jEX Recently, a surge of (pre)clinical compounds inhibiting the NLRP3 inflammasome, often featuring a hexahydroindacene ring system, has emerged. In a push for new chemotypes, AstraZeneca and Mitsubishi Tanabe have disclosed their clinical compound, AZD4144, which is currently in Ph. I trials in healthy volunteers. The discovery story, presented at the EFMC-ISMC 2024 Meeting in Rome, detailed their efforts to overcome phospholipidosis, genotoxicity, and hERG inhibition in a non-classical pharmacophore series. Read it on Drug Hunter | https://lnkd.in/gKNb7jEX

Novartis Continues to Fill Its Malaria Pipeline, with a Long Half-Life IV Compound for Severe Malaria | https://lnkd.in/g73TYuCF Infection with the malaria parasite, Plasmodium falciparum, is a leading cause of fatality in the tropical regions of the world, with over 240M infections and >600K deaths each year. Currently, over half of the world population is at risk of infection and with the rise of resistance against current treatments, the need for new antimalarials is clear. At the ACS Fall 2024 conference in Denver, CO, Novartis outlined the structure and discovery story of NVP-FVP954, a novel IV compound for severe malaria. Read our coverage to discover how the Novartis team used a curated phenotypic screen to identify high quality chemical matter, balanced potency with physicochemical properties and dealt with IV/IV disconnects. Read it on Drug Hunter | https://lnkd.in/g73TYuCF

Drugging GTPases Beyond KRAS | https://lnkd.in/gz6gaadu Thu, Nov 7, 2024  8 AM PDT / 11 AM EDT / 5 PM CEST The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of GEFs (guanine exchange factors) and GAPs (GTPase-activating proteins). These comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of GTP and lack of allosteric regulatory sites. This paradigm was recently challenged by the discovery of a cryptic allosteric pocket in the Switch II region of KRAS. In this Flash Talk, Johannes Morstein will discuss the question if similar pockets are present in GTPases beyond KRAS. He will detail how the team systematically surveyed members of the Ras-, Rho-, and Rab-family of GTPases and found that many GTPases exhibit targetable Switch II pockets. He will explain the notable differences in the composition and conservation of key residues. Johannes will detail how these findings set the stage for the development of optimized inhibitors for many members of this previously undruggable family. Don't miss this opportunity to learn about how researchers are breaking into previously undruggable space leveraging innovative analytic technologies. Johannes will also be available for a Q&A session. So be sure to bring your questions about drugging ‘undruggable’ proteins in the GTPase family. This is a live-only event you won't want to miss! Register here: https://lnkd.in/gz6gaadu

September 2024 Annotated Searchable Patent Table | https://lnkd.in/gJ_a9MXb Staying on top of the latest IP advances in drug discovery is no small feat, so we’ve made it easier for you. Our team has sifted through thousands of recently published patents to compile a curated list of over 200 significant IP disclosures from September 2024. Each entry is accompanied by a detailed annotation to help you quickly grasp the essentials. Look out for upcoming articles where we’ll explore some of our top picks in depth! Read it on Drug Hunter | https://lnkd.in/gJ_a9MXb

A Syk Inhibitor for the Treatment of Autoimmune Disorders | https://lnkd.in/gn_ZYJY9 Sovleplenib (HMPL-523) is an orally bioavailable inhibitor of Syk that is being developed by HUTCHMED and is currently in Ph. II and Ph. III clinical trials for several autoimmune diseases. In 2018, Rigel Pharmaceuticals Inc.'s phosphate prodrug, fostamatinib (Tavalisse®), was the first Syk inhibitor to receive US FDA marketing approval for the treatment of primary ITP, but it is dose-limited in humans due in part to its inhibitory activity of KDR and RET kinase. Derived from an HTS hit and SAR optimization, the discovery story of sovleplenib serves as an excellent case study on how to design a next-generation Syk inhibitor devoid of off-target kinase activity, mitigated hERG activity, and more. Full article: https://lnkd.in/gn_ZYJY9

A Potential First-in-Class Selective CK1α Molecular Glue Degrader | https://lnkd.in/g4qXjR5r BMS-986397 is a potential first-in-class molecular glue degrader targeting CK1α, a key player in promoting tumor growth through the suppression of p53 by MDM2 and MDMX. Since AML typically has a low TP53 mutation rate (~13%), activating the p53 pathway in WT TP53 AML is a promising therapeutic strategy. However, previous p53 activators have been limited by hematological toxicities. The targeted degradation of CK1α offers an alternative approach to overcoming these challenges. The BMS team aimed to create a CELMoD® that selectively degrades CK1α. Learn how Bristol Myers Squibb overcame bioavailability challenges, optimized off-target degradation profiles, how the ternary complex is formed, and much more! Read it on Drug Hunter | https://lnkd.in/g4qXjR5r