2. Academic Validation
  3. Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations

Discovery and Optimization of Potent, Efficacious and Selective Inhibitors Targeting EGFR Exon20 Insertion Mutations

  • J Med Chem. 2024 Jun 13;67(11):8988-9027. doi: 10.1021/acs.jmedchem.4c00227.
Clare Thomson 1,  Peter Barton 1,  Erin Braybrooke 1,  Nicola Colclough 1,  Zhiqiang Dong 2,  Laura Evans 1,  Nicolas Floc'h 1,  Carine Guérot 1,  David Hargreaves 1,  Puneet Khurana 1,  Songlei Li 2,  Xiuwei Li 2,  Andrew Lister 1,  William McCoull 1,  Lisa McWilliams 1,  Jonathan P Orme 1,  Martin J Packer 1,  Aisha M Swaih 1,  Richard A Ward 1,  Poppy Winlow 1,  Yang Ye 2
Affiliations

Affiliations

  • 1 AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, United Kingdom.
  • 2 Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
PMID: 38770784 DOI: 10.1021/acs.jmedchem.4c00227
Abstract

Herein, we report the identification and optimization of a series of potent inhibitors of EGFR Exon20 insertions with significant selectivity over wild-type EGFR. A strategically designed HTS campaign, multiple iterations of structure-based drug design (SBDD), and tactical linker replacement led to a potent and wild-type selective series of molecules and ultimately the discovery of 36. Compound 36 is a potent and selective inhibitor of EGFR Exon20 insertions and has demonstrated encouraging efficacy in NSCLC EGFR CRISPR-engineered H2073 xenografts that carry an SVD Exon20 insertion and reduced efficacy in a H2073 wild-type EGFR xenograft model compared to CLN-081 (5), indicating that 36 may have lower EGFR wild-type associated toxicity.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163663
    EGFR外显子20插入抑制剂
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