1. Academic Validation
  2. Genomic Discovery and Structure-Activity Exploration of a Novel Family of Enzyme-Activated Covalent Cyclin-Dependent Kinase Inhibitors

Genomic Discovery and Structure-Activity Exploration of a Novel Family of Enzyme-Activated Covalent Cyclin-Dependent Kinase Inhibitors

  • J Med Chem. 2024 Aug 8;67(15):13147-13173. doi: 10.1021/acs.jmedchem.4c01095.
Jack R Davison 1 Michalis Hadjithomas 1 Stuart P Romeril 1 Yoon Jong Choi 1 Keith W Bentley 1 John B Biggins 1 Nadia Chacko 1 M Paola Castaldi 1 Lawrence K Chan 1 Jared N Cumming 1 Thomas D Downes 1 Eric L Eisenhauer 1 Fan Fei 1 Benjamin M Fontaine 1 Venkatesh Endalur Gopinarayanan 1 Srishti Gurnani 1 Audrey Hecht 1 Christopher J Hosford 1 Ashraf Ibrahim 1 Annika Jagels 1 Camil Joubran 1 Ji-Nu Kim 1 John P Lisher 1 Daniel D Liu 1 James T Lyles 1 Matteo N Mannara 1 Gordon J Murray 1 Emilia Musial 1 Mengyao Niu 1 Roberto Olivares-Amaya 1 Marielle Percuoco 1 Susanne Saalau 1 Kristen Sharpe 1 Anjali V Sheahan 1 Neroshan Thevakumaran 1 James E Thompson 1 Dawn A Thompson 1 Aric Wiest 1 Stephen A Wyka 1 Jason Yano 1 Gregory L Verdine 1 2
Affiliations

Affiliations

  • 1 LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.
  • 2 Departments of Chemistry and Chemical Biology, and Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
Abstract

Fungi have historically been the source of numerous important medicinal compounds, but full exploitation of their genetic potential for drug development has been hampered in traditional discovery paradigms. Here we describe a radically different approach, top-down drug discovery (TD3), starting with a massive digital search through a database of over 100,000 fully genomicized fungi to identify loci encoding molecules with a predetermined human target. We exemplify TD3 by the selection of cyclin-dependent kinases (CDKs) as targets and the discovery of two molecules, 1 and 2, which inhibit therapeutically important human CDKs. 1 and 2 exhibit a remarkable mechanism, forming a site-selective covalent bond to the CDK active site Lys. We explored the structure-activity relationship via semi- and total synthesis, generating an analog, 43, with improved kinase selectivity, bioavailability, and efficacy. This work highlights the power of TD3 to identify mechanistically and structurally novel molecules for the development of new medicines.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162785
    CDK Inhibitor
    CDK