5UGA

Crystal structure of the EGFR kinase domain (L858R, T790M, V948R) in complex with 4-(4-{[2-{[(3S)-1-acetylpyrrolidin-3-yl]amino}-9-(propan-2-yl)-9H-purin-6-yl]amino}phenyl)-1-methylpiperazin-1-ium

Summary for 5UGA

• Entry DOI: 10.2210/pdb5uga/pdb
• Related: 5UG8 5UG9 5UGB 5UGC
• Descriptor: Epidermal growth factor receptor, 4-(4-{[2-{[(3S)-1-acetylpyrrolidin-3-yl]amino}-9-(propan-2-yl)-9H-purin-6-yl]amino}phenyl)-1-methylpiperazin-1-ium, SULFATE ION, ... (5 entities in total)
• Functional Keywords: kinase, covalent inhibitor, lung cancer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted: P00533
• Total number of polymer chains: 1
• Total formula weight: 38526.47

Authors

Gajiwala, K.S.,Ferre, R.A. (deposition date: 2017-01-07, release date: 2017-03-22, Last modification date: 2024-03-06)

Primary citation

Planken, S.,Behenna, D.C.,Nair, S.K.,Johnson, T.O.,Nagata, A.,Almaden, C.,Bailey, S.,Ballard, T.E.,Bernier, L.,Cheng, H.,Cho-Schultz, S.,Dalvie, D.,Deal, J.G.,Dinh, D.M.,Edwards, M.P.,Ferre, R.A.,Gajiwala, K.S.,Hemkens, M.,Kania, R.S.,Kath, J.C.,Matthews, J.,Murray, B.W.,Niessen, S.,Orr, S.T.,Pairish, M.,Sach, N.W.,Shen, H.,Shi, M.,Solowiej, J.,Tran, K.,Tseng, E.,Vicini, P.,Wang, Y.,Weinrich, S.L.,Zhou, R.,Zientek, M.,Liu, L.,Luo, Y.,Xin, S.,Zhang, C.,Lafontaine, J.
Discovery of N-((3R,4R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1H-pyrazol-4-yl)amino)-9-methyl-9H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR.
J. Med. Chem., 60:3002-3019, 2017

PubMed Abstract: Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.

PubMed: 28287730
DOI: 10.1021/acs.jmedchem.6b01894

Experimental method

X-RAY DIFFRACTION (1.82 Å)