2. Academic Validation
  3. Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance

Potent and Selective Inhibitors of the Epidermal Growth Factor Receptor to Overcome C797S-Mediated Resistance

  • J Med Chem. 2021 Sep 23;64(18):13704-13718. doi: 10.1021/acs.jmedchem.1c01055.
M Raymond V Finlay 1,  Peter Barton 1,  Sue Bickerton 1,  Michal Bista 2,  Nicola Colclough 1,  Darren A E Cross 1,  Laura Evans 1,  Nicolas Floc'h 1,  Clare Gregson 1,  Carine M Guérot 1,  David Hargreaves 2,  Xiaoming Kang 3,  Eva M Lenz 1,  Xu Li 3,  Yi Liu 3,  Olivier Lorthioir 1,  Matthew J Martin 1,  Darren McKerrecher 1,  Claire McWhirter 2,  Daniel O'Neill 2,  Jonathan P Orme 2,  Arash Mosallanejad 1,  Amar Rahi 1,  Paul D Smith 1,  Verity Talbot 2,  Richard A Ward 1,  Gail Wrigley 1,  Marta Wylot 1,  Lin Xue 3,  Tieguang Yao 3,  Yang Ye 3,  Xiliang Zhao 3
Affiliations

Affiliations

  • 1 AstraZeneca, Oncology R&D, Research & Early Development, Darwin Building, 310, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
  • 2 AstraZeneca, Discovery Sciences, Research & Early Development, Darwin Building, 310, Cambridge Science Park, Milton Road, Cambridge CB4 0WG, U.K.
  • 3 Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
PMID: 34491761 DOI: 10.1021/acs.jmedchem.1c01055
Abstract

The epidermal growth factor receptor (EGFR) harboring activating mutations is a clinically validated target in non-small-cell lung Cancer, and a number of inhibitors of the EGFR tyrosine kinase domain, including osimertinib, have been approved for clinical use. Resistance to these therapies has emerged due to a variety of molecular events including the C797S mutation which renders third-generation C797-targeting covalent EGFR inhibitors considerably less potent against the target due to the loss of the key covalent-bond-forming residue. We describe the medicinal chemistry optimization of a biochemically potent but modestly cell-active, reversible EGFR inhibitor starting point with sub-optimal physicochemical properties. These studies culminated in the identification of compound 12 that showed improved cell potency, oral exposure, and in vivo activity in clinically relevant EGFR-mutant-driven disease models, including an Exon19 deletion/T790M/C797S triple-mutant mouse xenograft model.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-115716
    98.42%, EGFR抑制剂
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