Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an In Silico Enabled Drug Discovery Platform

  • J Med Chem. 2024 Dec 26;67(24):21811-21840. doi: 10.1021/acs.jmedchem.4c01405.
Hideyuki Igawa  1 ,  Zef A Konst  1 ,  Eric Therrien  1 ,  Mee Shelley  2 ,  Heidi Koldsø  1 ,  Pieter H Bos  1 ,  Ana Negri  1 ,  Andreas Verras  1 ,  Jiaye Guo  1 ,  Markus K Dahlgren  1 ,  Adam Levinson  1 ,  Brendan T Parr  2 ,  Suresh E Kurhade  3 ,  Prashant Latthe  4 ,  Rajesha Shetty  4 ,  Sridhar Santhanakrishnan  4 ,  Katherine Amberg-Johnson  1 ,  Alan S Futran  1 ,  Christian Atsriku  1 ,  Robert D Pelletier  1 ,  Zhijian Liu  1 ,  Jeffrey A Bell  1 ,  Sathesh Bhat  1 ,  Mats Svensson  1 ,  Aleksey I Gerasyuto  1
Affiliations
  • 1. Schrödinger Inc., New York, New York 10036, United States.
  • 2. Schrödinger Inc., Portland, Oregon 97204, United States.
  • 3. Schrödinger Inc., Hyderabad, Telangana 50081, India.
  • 4. Syngene International Ltd., Bengaluru, Karnataka 560099, India.
PMID: 39666597 DOI: 10.1021/acs.jmedchem.4c01405
Abstract

Despite the success of first, second, and third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small cell lung Cancer with classical EGFR mutations (L858R or Exon 19 deletions), disease progression occurs due to the acquisition of T790M and C797S resistance. Herein, we report a physics-based computationally driven lead identification approach that identified structurally unique imidazo[3.2-b]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S. During profiling of imidazo[3.2-b]pyrazoles, we elucidated the bioactivation mechanism causing CYP3A4/5 time-dependent inhibition (TDI) and found key modifications to mitigate the TDI. Compound 31 inhibited EGFR L858R/T790M/C797S in biochemical assays with a Ki = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC50 = 56.9 nM. The deuterated analogue of 31 (38) demonstrated dose-dependent tumor growth inhibition in a Ba/F3 EGFR del19/T790M/C797S CDX model by 47% at 50 mg/kg BID and 92% at 100 mg/kg BID.

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