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
  • 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162431
    Calderasib
    99.82%, KRAS G12C Inhibitor
    target: Ras
    Research Areas: Cancer