2. Academic Validation
  3. Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC

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

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: davida_scott@dfci.harvard.edu.
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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