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!

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

A Potential First-in-Class ENT1 Inhibitor for Immuno-oncology Indications Derived from Dilazep | https://lnkd.in/eW-BXDf3 EOS-984 is an oral, potential first-in-class, highly selective ENT1 inhibitor from iTeos Therapeutics currently in clinical trials for advanced solid tumors. The drug, which was identified through SBDD and optimization of the vasodilator dilazep, targets the immunosuppressive effects of adenosine, which helps tumors evade immune detection. iTeos Therapeutics presented the discovery story of EOS-984 at the American Chemical Society Fall 2024 Meeting in Denver, offering an excellent case study on the importance of understanding a molecule's bioactive conformation to reduce the entropy of binding and enhance potency. The presentation also highlighted strategies to troubleshoot carboxylesterase-mediated hydrolysis in ester-containing series. Full article: https://lnkd.in/eW-BXDf3

Gilead Utilizes A Counterintuitive Approach to Improve the Metabolic Stability of an HIV Protease Inhibitor | https://lnkd.in/gXqgrPN5 Many drug discovery projects struggle with CYP-mediated metabolism, especially in the peptidomimetic space. Gilead Sciences has taken a counterintuitive approach to this problem with their novel HIV protease inhibitor, elunonavir. Disclosed at the Fall 2024 ACS meeting in Denver, this compound utilizes insights and structural elements from Gilead’s NS5A inhibitor program to deliver a peptidomimetic with >2 week human half-life. Read our coverage to discover how extensive MetID work with a “hot” in vitro clearance assay was used to drive the lead optimization of these unusual-looking compounds Read it on Drug hunter | https://lnkd.in/gXqgrPN5

📣Reminder📣 The Chemist's Playbook: Impactful Bioisosteres for Modern Drug Design | https://lnkd.in/gz6gaadu Thu, Oct 24, 2024  8 AM PDT / 11 AM EDT / 5 PM CEST Are you interested in the history of bioisosteres and would like to understand when and how to successfully use bioisosteres on your project? Join us this Thursday for a Flash Talk with Nicholas A. Meanwell where he will explore the history of bioisosterism. He will present a series of case studies featuring both established and emerging bioisosteres, highlighting how they have been utilized to address various challenges in drug discovery.  You will see examples for isosteres of carboxylic acids, amides, phosphates, phenyl groups and hydrogens. The journey will focus on molecule case studies that had an impact on the contemporary pharmacopeia. Don't miss this opportunity to learn from a renowned expert in the field. Nick will be available for a live Q&A after the presentation. This is an Flash Talk you don't want to miss. Register here: https://lnkd.in/gz6gaadu

Molecules of the Month – September 2024 | https://lnkd.in/gjAbvjaF 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, and Boehringer Ingelheim's pan-KRAS heterobifunctional degrader. Read the full article to find out what compounds made our September 2024 Molecules of the Month list, and check out recent articles for each. Full Article: https://lnkd.in/gjAbvjaF

A First-In-Class Intracellular Checkpoint Inhibitor of DGK ⍺ and ζ Stemming from Phenotypic Screening | https://lnkd.in/g78zqBCU BMS-986408 is an oral, dual DGK ⍺ and ζ inhibitor currently in a Ph. I/II clinical trial as a single agent and in combination with PD-1 inhibitor nivolumab or with nivolumab and CTLA-4 inhibitor ipilimumab 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. Bristol Myers Squibb presented the discovery story of BMS-986408 at the American Chemical Society Fall 2024 Meeting in Denver, which was 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). Full article: https://lnkd.in/g78zqBCU