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

Autor: Igawa H; Schrödinger Inc., New York, New York 10036, United States., Konst ZA; Schrödinger Inc., New York, New York 10036, United States., Therrien E; Schrödinger Inc., New York, New York 10036, United States., Shelley M; Schrödinger Inc., Portland, Oregon 97204, United States., Koldsø H; Schrödinger Inc., New York, New York 10036, United States., Bos PH; Schrödinger Inc., New York, New York 10036, United States., Negri A; Schrödinger Inc., New York, New York 10036, United States., Verras A; Schrödinger Inc., New York, New York 10036, United States., Guo J; Schrödinger Inc., New York, New York 10036, United States., Dahlgren MK; Schrödinger Inc., New York, New York 10036, United States., Levinson A; Schrödinger Inc., New York, New York 10036, United States., Parr BT; Schrödinger Inc., Portland, Oregon 97204, United States., Kurhade SE; Schrödinger Inc., Hyderabad, Telangana 50081, India., Latthe P; Syngene International Ltd., Bengaluru, Karnataka 560099, India., Shetty R; Syngene International Ltd., Bengaluru, Karnataka 560099, India., Santhanakrishnan S; Syngene International Ltd., Bengaluru, Karnataka 560099, India., Amberg-Johnson K; Schrödinger Inc., New York, New York 10036, United States., Futran AS; Schrödinger Inc., New York, New York 10036, United States., Atsriku C; Schrödinger Inc., New York, New York 10036, United States., Pelletier RD; Schrödinger Inc., New York, New York 10036, United States., Liu Z; Schrödinger Inc., New York, New York 10036, United States., Bell JA; Schrödinger Inc., New York, New York 10036, United States., Bhat S; Schrödinger Inc., New York, New York 10036, United States., Svensson M; Schrödinger Inc., New York, New York 10036, United States., Gerasyuto AI; Schrödinger Inc., New York, New York 10036, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2024 Dec 12. Date of Electronic Publication: 2024 Dec 12.
DOI: 10.1021/acs.jmedchem.4c01405
Abstrakt: 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 K i = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC 50 = 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.
Databáze: MEDLINE
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