2. Academic Validation
  3. Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor

Discovery of MK-1084: An Orally Bioavailable and Low-Dose KRASG12C Inhibitor

  • J Med Chem. 2024 Jul 11;67(13):11024-11052. doi: 10.1021/acs.jmedchem.4c00572.
Xiaoshen Ma 1,  David L Sloman 1,  Ruchia Duggal 2,  Kenneth D Anderson 3,  Jeanine E Ballard 2,  Indu Bharathan 1,  Christopher Brynczka 4,  Symon Gathiaka 1,  Timothy J Henderson 1,  Thomas W Lyons 5,  Richard Miller 6,  Erik V Munsell 7,  Peter Orth 8,  Ryan D Otte 1,  Anandan Palani 1,  Danica A Rankic 5,  Michelle R Robinson 3,  Aaron C Sather 5,  Nicolas Solban 6,  Xuelei Sherry Song 6,  Xin Wen 5,  Zangwei Xu 6,  Yi Yang 6,  Ruojing Yang 6,  Phil J Day 9,  Alexander Stoeck 10,  David Jonathan Bennett 1,  Yongxin Han 1
Affiliations

Affiliations

  • 1 Department of Discovery Chemistry, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
  • 2 Department of Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
  • 3 Department of Pharmacokinetics, Dynamics, Metabolism and Bioanalytics, Merck & Co., Inc., 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
  • 4 Department of Nonclinical Drug Safety, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
  • 5 Department of Process Research and Development, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
  • 6 Department of Discovery Quantitative Biosciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
  • 7 Department of Discovery Pharmaceutical Sciences, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
  • 8 Department of Analytical Research and Development, Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey 07065, United States.
  • 9 Department of Structural Biology, Astex Pharmaceuticals, 436 Cambridge Science Park, Cambridge CB4 0QA, U.K.
  • 10 Department of Discovery Biology, Merck & Co., Inc., 33 Ave. Louis Pasteur, Boston, Massachusetts 02215, United States.
PMID: 38924388 DOI: 10.1021/acs.jmedchem.4c00572
Abstract

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 KRASG12C 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162431
    99.82%, KRAS G12C Inhibitor
    Ras