9D3W
CRYSTAL STRUCTURE OF EGFR(L858R/T790M/C797S) IN COMPLEX WITH AUR-8250
This is a non-PDB format compatible entry.
Summary for 9D3W
| Entry DOI | 10.2210/pdb9d3w/pdb |
| Descriptor | Epidermal growth factor receptor, (4S)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-N-{2-[(3S,4R)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl}-2-methyl-1H-imidazo[1,2-b]pyrazol-6-amine, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | protein kinase, inhibitor, kinase domain, transferase, transferase-inhibitor complex, transferase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 38090.71 |
| Authors | |
| Primary citation | 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 Cited by 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: 39666597DOI: 10.1021/acs.jmedchem.4c01405 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.53 Å) |
Structure validation
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