2XP2

Structure of the Human Anaplastic Lymphoma Kinase in Complex with Crizotinib (PF-02341066)

Summary for 2XP2

• Entry DOI: 10.2210/pdb2xp2/pdb
• Descriptor: TYROSINE-PROTEIN KINASE RECEPTOR, 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-amine (3 entities in total)
• Functional Keywords: crizotinib, transferase
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 37359.69

Authors

McTigue, M.,Deng, Y.,Liu, W.,Brooun, A.,Timofeevski, S.,Marrone, T.,Cui, J.J. (deposition date: 2010-08-24, release date: 2010-09-15, Last modification date: 2023-12-20)

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

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: 21812414
DOI: 10.1021/JM2007613

Experimental method

X-RAY DIFFRACTION (1.9 Å)