9D3V

CRYSTAL STRUCTURE OF EGFR(L858R/T790M/C797S) IN COMPLEX WITH AUR-3418

これはPDB形式変換不可エントリーです。

9D3V の概要

• エントリーDOI: 10.2210/pdb9d3v/pdb
• 分子名称: Epidermal growth factor receptor, (4S)-N-[2-(4-methoxypiperidin-1-yl)pyrimidin-4-yl]-2-methyl-1-(propan-2-yl)-1H-imidazo[1,2-b]pyrazol-6-amine, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: protein kinase, inhibitor, kinase domain, transferase, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37974.62

構造登録者

Bell, J.A. (登録日: 2024-08-12, 公開日: 2025-03-05)

主引用文献

Igawa, H.,Konst, Z.A.,Therrien, E.,Shelley, M.,Koldso, H.,Bos, P.H.,Negri, A.,Verras, A.,Guo, J.,Dahlgren, M.K.,Levinson, A.,Parr, B.T.,Kurhade, S.E.,Latthe, P.,Shetty, R.,Santhanakrishnan, S.,Amberg-Johnson, K.,Futran, A.S.,Atsriku, C.,Pelletier, R.D.,Liu, Z.,Bell, J.A.,Bhat, S.,Svensson, M.,Gerasyuto, A.I.
Discovery of a Novel Mutant-Selective Epidermal Growth Factor Receptor Inhibitor Using an In Silico Enabled Drug Discovery Platform.
J.Med.Chem., 67:21811-21840, 2024

PubMed 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-]pyrazoles as reversible and wild-type-sparing EGFR TKIs of classical mutations bearing both T790M and C797S. During profiling of imidazo[3.2-]pyrazoles, we elucidated the bioactivation mechanism causing CYP3A4/5 time-dependent inhibition (TDI) and found key modifications to mitigate the TDI. Compound inhibited EGFR L858R/T790M/C797S in biochemical assays with a = 2.1 nM and EGFR del19/T790M/C797S in a Ba/F3 cellular assay with an IC = 56.9 nM. The deuterated analogue of () 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.

PubMed: 39666597
DOI: 10.1021/acs.jmedchem.4c01405

実験手法

X-RAY DIFFRACTION (2.32 Å)