1. Academic Validation
  2. Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations

Highly Optimized CNS Penetrant Inhibitors of EGFR Exon20 Insertion Mutations

  • J Med Chem. 2025 Feb 13;68(3):3700-3748. doi: 10.1021/acs.jmedchem.4c02811.
William McCoull 1 Clare Thomson 1 Erin Braybrooke 1 Christina Chan 1 Nicola Colclough 1 Miguel A Cortés González 2 Sabina Cosulich 1 Nichola L Davies 1 Nicolas Floc'h 1 Ryan Greenwood 1 David Hargreaves 1 Peng Huang 3 Thomas A Hunt 1 Tony Johnson 1 Peter Johnström 4 2 Jason G Kettle 1 Mikhail Kondrashov 2 Demetrios H Kostomiris 5 Songlei Li 3 Andrew Lister 1 Scott Martin 1 Darren McKerrecher 1 Neville McLean 1 J Willem M Nissink 1 Jonathan P Orme 1 Paige Orwig 1 Martin J Packer 1 Stuart Pearson 1 Lina Qin 3 Catarina Felisberto-Rodrigues 1 Adriana Savoca 1 Magnus Schou 4 2 Stephen Stokes 1 Aisha M Swaih 1 Sara Talbot 1 Michael J Tucker 1 Richard A Ward 1 Emma Wadforth 1 Chunli Wang 3 Joanne Wilson 3 Yawen Yang 3
Affiliations

Affiliations

  • 1 AstraZeneca, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, U.K.
  • 2 Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet and Stockholm County Council, Stockholm SE-171 76, Sweden.
  • 3 Pharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, P. R. China.
  • 4 PET Science Centre, Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Stockholm SE-171 76, Sweden.
  • 5 Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
Abstract

Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether 23 and biaryl 36 as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne 5 which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CLint compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168876
    EGFR Ex20Ins突变体抑制剂