Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRAS G12C Inhibitor.

Autor:	Ma X; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Sloman DL; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Duggal R; Department of Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Anderson KD; Department of Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Ballard JE; Department of Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Bharathan I; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Brynczka C; Department of Nonclinical Drug Safety, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Gathiaka S; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Henderson TJ; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Lyons TW; Department of Process Research and Development, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Miller R; Department of Discovery Quantitative Biosciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Munsell EV; Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Orth P; Department of Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey 07065, United States., Otte RD; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Palani A; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Rankic DA; Department of Process Research and Development, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Robinson MR; Department of Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States., Sather AC; Department of Process Research and Development, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Solban N; Department of Discovery Quantitative Biosciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Song XS; Department of Discovery Quantitative Biosciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Wen X; Department of Process Research and Development, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Xu Z; Department of Discovery Quantitative Biosciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Yang Y; Department of Discovery Quantitative Biosciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Yang R; Department of Discovery Quantitative Biosciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Day PJ; Department of Structural Biology, Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K., Stoeck A; Department of Discovery Biology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Bennett DJ; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States., Han Y; Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Jul 11; Vol. 67 (13), pp. 11024-11052. Date of Electronic Publication: 2024 Jun 26.
DOI:	10.1021/acs.jmedchem.4c00572
Abstrakt:	Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRAS G12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.
Databáze:	MEDLINE
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