2WKM
X-ray Structure of PHA-00665752 bound to the kinase domain of c-Met
Summary for 2WKM
| Entry DOI | 10.2210/pdb2wkm/pdb |
| Related | 1FYR 1R0P 1R1W 1SHY 1SSL 1UX3 2CEW 2G15 2UZX 2UZY 2WD1 2WGJ |
| Descriptor | HEPATOCYTE GROWTH FACTOR RECEPTOR, (3Z)-5-[(2,6-DICHLOROBENZYL)SULFONYL]-3-[(3,5-DIMETHYL-4-{[(2S)-2-(PYRROLIDIN-1-YLMETHYL)PYRROLIDIN-1-YL]CARBONYL}-1H-PYRROL-2-YL)METHYLIDENE]-1,3-DIHYDRO-2H-INDOL-2-ONE (3 entities in total) |
| Functional Keywords | hepatocyte growth factor receptor, c-met, kinase, inhibitor, transferase |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 35521.02 |
| Authors | McTigue, M.,Grodsky, N.,Ryan, K.,Cui, J.J. (deposition date: 2009-06-15, release date: 2010-08-25, Last modification date: 2023-12-13) |
| Primary citation | Cui, J.J.,Tran-Dube, M.,Shen, H.,Nambu, M.,Kung, P.P.,Pairish, M.,Jia, L.,Meng, J.,Funk, L.,Botrous, I.,Mctigue, M.,Grodsky, N.,Ryan, K.,Padrique, E.,Alton, G.,Timofeevski, S.,Yamazaki, S.,Li, Q.,Zou, H.,Christensen, J.,Mroczkowski, B.,Bender, S.,Kania, R.S.,Edwards, M.P. Structure Based Drug Design of Crizotinib (Pf-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (C-met) Kinase and Anaplastic Lymphoma Kinase (Alk). J.Med.Chem, 54:6342-, 2011 Cited by PubMed Abstract: Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties. PubMed: 21812414DOI: 10.1021/JM2007613 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
Download full validation report
