5CAV

EGFR kinase domain with compound 41a

Summary for 5CAV

• Entry DOI: 10.2210/pdb5cav/pdb
• Descriptor: Epidermal growth factor receptor, (1R)-1-{6-({2-[(3R,4S)-3-fluoro-4-methoxypiperidin-1-yl]pyrimidin-4-yl}amino)-1-[(2S)-1,1,1-trifluoropropan-2-yl]-1H-imidazo[4,5-c]pyridin-2-yl}ethanol (3 entities in total)
• Functional Keywords: protein kinase inhibitor, 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: 38132.90

Authors

Eigenbrot, C.,Yu, C. (deposition date: 2015-06-30, release date: 2015-10-28, Last modification date: 2024-03-06)

Primary citation

Heald, R.,Bowman, K.K.,Bryan, M.C.,Burdick, D.,Chan, B.,Chan, E.,Chen, Y.,Clausen, S.,Dominguez-Fernandez, B.,Eigenbrot, C.,Elliott, R.,Hanan, E.J.,Jackson, P.,Knight, J.,La, H.,Lainchbury, M.,Malek, S.,Mann, S.,Merchant, M.,Mortara, K.,Purkey, H.,Schaefer, G.,Schmidt, S.,Seward, E.,Sideris, S.,Shao, L.,Wang, S.,Yeap, K.,Yen, I.,Yu, C.,Heffron, T.P.
Noncovalent Mutant Selective Epidermal Growth Factor Receptor Inhibitors: A Lead Optimization Case Study.
J.Med.Chem., 58:8877-8895, 2015

PubMed Abstract: Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

PubMed: 26455919
DOI: 10.1021/acs.jmedchem.5b01412

Experimental method

X-RAY DIFFRACTION (2.73 Å)