Genomic Discovery and Structure-Activity Exploration of a Novel Family of Enzyme-Activated Covalent Cyclin-Dependent Kinase Inhibitors.
| Title: | Genomic Discovery and Structure-Activity Exploration of a Novel Family of Enzyme-Activated Covalent Cyclin-Dependent Kinase Inhibitors. |
|---|---|
| Authors: | Davison JR; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Hadjithomas M; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Romeril SP; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Choi YJ; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Bentley KW; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Biggins JB; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Chacko N; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Castaldi MP; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Chan LK; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Cumming JN; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Downes TD; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Eisenhauer EL; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Fei F; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Fontaine BM; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Endalur Gopinarayanan V; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Gurnani S; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Hecht A; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Hosford CJ; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Ibrahim A; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Jagels A; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Joubran C; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Kim JN; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Lisher JP; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Liu DD; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Lyles JT; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Mannara MN; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Murray GJ; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Musial E; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Niu M; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Olivares-Amaya R; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Percuoco M; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Saalau S; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Sharpe K; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Sheahan AV; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Thevakumaran N; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Thompson JE; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Thompson DA; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Wiest A; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Wyka SA; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Yano J; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; Verdine GL; LifeMine Therapeutics, 30 Acorn Park Drive, Cambridge, Massachusetts 02140, United States.; 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. |
| Source: | Journal of medicinal chemistry [J Med Chem] 2024 Aug 08; Vol. 67 (15), pp. 13147-13173. Date of Electronic Publication: 2024 Jul 30. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | Protein Kinase Inhibitors*/pharmacology ; Protein Kinase Inhibitors*/chemistry ; Protein Kinase Inhibitors*/chemical synthesis ; Cyclin-Dependent Kinases*/antagonists & inhibitors ; Cyclin-Dependent Kinases*/metabolism ; Drug Discovery*; Genomics/methods ; Humans ; Structure-Activity Relationship ; Animals ; Models, Molecular |
| 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. |
| References: | Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17195-17203. (PMID: 32606248); Proc Natl Acad Sci U S A. 2023 Nov 28;120(48):e2310522120. (PMID: 37983497); Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):173-8. (PMID: 24347635); Anal Biochem. 2005 Feb 15;337(2):351-3. (PMID: 15691518); Org Lett. 2016 Sep 2;18(17):4340-3. (PMID: 27537356); Chem Rev. 2000 Oct 11;100(10):3801-26. (PMID: 11749328); Cell Commun Signal. 2018 May 24;16(1):23. (PMID: 29793495); Saudi Pharm J. 2023 Jun;31(6):795-800. (PMID: 37228328); Molecules. 2023 Jan 10;28(2):. (PMID: 36677748); Curr Protoc Pharmacol. 2019 Sep;86(1):e67. (PMID: 31539923); Nat Rev Cancer. 2009 Mar;9(3):153-66. (PMID: 19238148); J Nat Prod. 2023 Aug 25;86(8):2046-2053. (PMID: 37566707); J Nat Prod. 2020 Mar 27;83(3):770-803. (PMID: 32162523); Annu Rev Biochem. 2012;81:587-613. (PMID: 22482904); Nat Rev Drug Discov. 2021 Jul;20(7):551-569. (PMID: 34002056); IMA Fungus. 2016 Jun;7(1):75-117. (PMID: 27433442); Science. 2015 May 22;348(6237):921-5. (PMID: 25999509); J Immunol. 2013 Dec 15;191(12):5785-91. (PMID: 24319282); Nat Rev Drug Discov. 2003 Jul;2(7):517-26. (PMID: 12815379); Clin Cancer Res. 2013 Dec 1;19(23):6404-18. (PMID: 24298071); Mol Cell. 2007 Nov 30;28(4):614-23. (PMID: 18042456); Cell. 2021 Jan 7;184(1):3-9. (PMID: 33417864); Nat Rev Cancer. 2009 Jan;9(1):28-39. (PMID: 19104514); Nat Chem Biol. 2021 Apr;17(4):456-464. (PMID: 33526892); J Proteome Res. 2015 Mar 6;14(3):1574-86. (PMID: 25660469); Trends Genet. 2010 Oct;26(10):449-57. (PMID: 20739089); J Ind Microbiol Biotechnol. 2010 Jul;37(7):643-72. (PMID: 20446033); Biochemistry. 2000 Nov 14;39(45):13625-32. (PMID: 11076500); Int J Antimicrob Agents. 2007 Jan;29(1):3-8. (PMID: 17137753); Nat Prod Rep. 2020 Jul 1;37(7):879-892. (PMID: 31912842); Antonie Van Leeuwenhoek. 2000 Dec;78(3-4):287-95. (PMID: 11386351); J Am Chem Soc. 2003 Nov 26;125(47):14248-9. (PMID: 14624552); Cell. 2017 Jul 27;170(3):564-576.e16. (PMID: 28753430); J Biol Chem. 1997 May 9;272(19):12738-46. (PMID: 9139732); Drug Discov Today. 2020 Feb;25(2):406-413. (PMID: 31839441); PLoS Comput Biol. 2005 Oct;1(5):e49. (PMID: 16244704); J Med Chem. 2004 Dec 2;47(25):6338-48. (PMID: 15566303); ACS Chem Biol. 2018 Jun 15;13(6):1426-1437. (PMID: 29763292); Nat Rev Drug Discov. 2021 Mar;20(3):200-216. (PMID: 33510482) |
| Substance Nomenclature: | 0 (Protein Kinase Inhibitors); EC 2.7.11.22 (Cyclin-Dependent Kinases) |
| Entry Date(s): | Date Created: 20240730 Date Completed: 20240808 Latest Revision: 20250908 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11320645 |
| DOI: | 10.1021/acs.jmedchem.4c01095 |
| PMID: | 39078366 |
| Database: | MEDLINE |
Journal Article