Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC

  • Bioorg Med Chem Lett. 2022 Jul 15;68:128718. doi: 10.1016/j.bmcl.2022.128718.
Thomas W Gero  1 ,  David E Heppner  1 ,  Tyler S Beyett  1 ,  Ciric To  2 ,  Seth C Azevedo  1 ,  Jaebong Jang  1 ,  Thomas Bunnell  1 ,  Frederic Feru  1 ,  Zhengnian Li  1 ,  Bo Hee Shin  2 ,  Kara M Soroko  3 ,  Prafulla C Gokhale  3 ,  Nathanael S Gray  1 ,  Pasi A Jänne  2 ,  Michael J Eck  1 ,  David A Scott  4
Affiliations
  • 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA.
  • 2. Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 3. Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston MA 02215, USA.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, 360 Longwood Ave, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 35378251 DOI: 10.1016/j.bmcl.2022.128718
Abstract

The C797S mutation confers resistance to covalent EGFR inhibitors used in the treatment of lung Tumors with the activating L858R mutation. Isoindolinones such as JBJ-4-125-02 bind in an allosteric pocket and are active against this mutation, with high selectivity over wild-type EGFR. The most potent examples we developed from that series have a potential chemical instability risk from the combination of the amide and phenol groups. We explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. The 5-F quinazolinone 34 demonstrated tumor regression in an H1975 efficacy model upon once daily oral dosing at 25 mg/kg.

Keywords
Allosteric inhibitor; EGFR; Kinase inhibitor; Non-small cell lung cancer; Quinazolinone.
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