Optimization of Covalent 6-Cyanoquinazoline KRASG12C Inhibitors for the Treatment of Solid Tumors

  • J Med Chem. 2026 Apr 23;69(8):9163-9195. doi: 10.1021/acs.jmedchem.5c03610.
Jesse P Waldo  1 ,  Paul J Krawczuk  1 ,  Christopher B Kelly  1 ,  Christopher G Callas  1 ,  Justin S Cisar  1 ,  Wendy Eccles  1 ,  Carlos A Guerrero  1 ,  Michael D Hack  2 ,  William M Jones  1 ,  Colleen E Keohane  1 ,  Lian-Sheng Li  3 ,  Sanath Meegalla  1 ,  Rosaura Padilla-Salinas  1 ,  Robert J Rosano  1 ,  Kirk W Shimkin  1 ,  Yvan R F Simonnet  1 ,  Doree Sitkoff  1 ,  Anasheh Sookezian  1 ,  Michael P Winters  1 ,  Tammy L Bush  1 ,  Sheldon T Cheung  1 ,  Amanda M Del Rosario  1 ,  Rasmus Hansen  3 ,  Matthew R Janes  3 ,  Haleema Janjua  1 ,  Faraz Kazmi  1 ,  Robert Kirkpatrick  1 ,  David La  2 ,  Ryan Lenhart  1 ,  Matthew V Lorenzi  1 ,  Yi Liu  3 ,  Natalie Mesens  4 ,  Cynthia M Milligan  1 ,  Heather Murrey  1 ,  Ulf Peters  3 ,  Pingda Ren  3 ,  Mark Richter  1 ,  Michele Rizzolio  2 ,  Swetha Rao  1 ,  Paul Shaffer  1 ,  Christopher F Stratton  1 ,  Lawrence M Szewczuk  1 ,  Jenny Wen  3 ,  Victoria Wong  1 ,  Carol Yanovich  1 ,  Sylvie Laquerre  1 ,  James P Edwards  2 ,  Kristi A Leonard  1
Affiliations
  • 1. Johnson & Johnson, 1400 McKean Road, Spring House, Pennsylvania 19477, United States.
  • 2. Johnson & Johnson, 3210 Merryfield Row, San Diego, California 92121, United States.
  • 3. Wellspring Biosciences, Inc., 3033 Science Park Road, San Diego, California 92121, United States.
  • 4. Johnson & Johnson, Turnhoutseweg 30, Beerse 2340, Belgium.
PMID: 41921095 DOI: 10.1021/acs.jmedchem.5c03610
Abstract

The KRASG12C mutation is a critical therapeutic target in the management of solid tumors, owing to its role in oncogenic signaling. Recent advances in covalent inhibitors that target mutant KRAS cysteine-12 have demonstrated the potential to halt aberrant signaling associated with this historically "undruggable" target. Here, we report the identification of 6-cyanoquinazoline covalent irreversible KRASG12C inhibitors. Lead optimization used structure-based design to identify novel switch-II pocket-binding motifs and in silico models to forecast in vitro metabolic stability and permeability. Human dose was improved by maximizing the rate of covalent modification (kobs/[I]) of KRASG12C-GDP, along with optimizing ADME parameters, to identify potent, orally bioavailable lead molecule 13de which demonstrated significant antitumor efficacy in the NCI-H1373 human lung adenocarcinoma xenograft model. Studies evaluating KRASG12C-GDP covalent target engagement, pharmacokinetics, and tumor growth inhibition estimated the efficacious human dose of 13de to be 192 mg administered once daily (QD), using allometric scaling.

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