2. Academic Validation
  3. Optimization of Covalent 6-Cyanoquinazoline KRASG12C Inhibitors for the Treatment of Solid Tumors

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

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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