2YFX

Structure of L1196M Mutant Anaplastic Lymphoma Kinase in Complex with Crizotinib

Summary for 2YFX

• Entry DOI: 10.2210/pdb2yfx/pdb
• Related: 2XP2 2YHV 4ANL 4ANQ 4CCB 4CCU 4CD0
• 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: nucleotide-binding, transferase, receptor
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 37377.73

Authors

McTigue, M.,Deng, Y.,Liu, W.,Brooun, A. (deposition date: 2011-04-08, release date: 2011-05-04, Last modification date: 2023-12-20)

Primary citation

Huang, Q.,Johnson, T.W.,Bailey, S.,Brooun, A.,Bunker, K.D.,Burke, B.J.,Collins, M.R.,Cook, A.S.,Cui, J.J.,Dack, K.N.,Deal, J.G.,Deng, Y.,Dinh, D.,Engstrom, L.D.,He, M.,Hoffman, J.,Hoffman, R.L.,Johnson, P.S.,Kania, R.S.,Lam, H.,Lam, J.L.,Le, P.T.,Li, Q.,Lingardo, L.,Liu, W.,Lu, M.W.,Mctigue, M.,Palmer, C.L.,Richardson, P.F.,Sach, N.W.,Shen, H.,Smeal, T.,Smith, G.L.,Stewart, A.E.,Timofeevski, S.,Tsaparikos, K.,Wang, H.,Zhu, H.,Zhu, J.,Zou, H.Y.,Edwards, M.P.
Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib.
J.Med.Chem., 57:1170-, 2014

PubMed Abstract: Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

PubMed: 24432909
DOI: 10.1021/JM401805H

Experimental method

X-RAY DIFFRACTION (1.7 Å)