4CD0

Structure of L1196M Mutant Human Anaplastic Lymphoma Kinase in Complex with 2-(5-(6-amino-5-((R)-1-(5-fluoro-2-(2H-1,2,3-triazol-2- yl)phenyl)ethoxy)pyridin-3-yl)-4-methylthiazol-2-yl)propane-1,2-diol

Summary for 4CD0

• Entry DOI: 10.2210/pdb4cd0/pdb
• Related: 4CCB 4CCU
• Descriptor: ALK TYROSINE KINASE RECEPTOR, (2R)-2-[5-(6-amino-5-{(1R)-1-[2-(1,3-dihydro-2H-1,2,3-triazol-2-yl)-5-fluorophenyl]ethoxy}pyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol (3 entities in total)
• Functional Keywords: transferase, receptor tyrosine kinase, inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 39086.70

Authors

McTigue, M.,Deng, Y.,Liu, W.,Brooun, A.,Stewart, A. (deposition date: 2013-10-29, release date: 2014-01-29, 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.,Cui, J.J.,Dack, K.N.,Deal, J.G.,Deng, Y.,Dinh, D.M.,Engstrom, L.D.,He, M.,Hoffman, J.,Hoffman, R.L.,Shen, H.,Johnson, P.,Kania, R.S.,Lam, H.,Lam, J.L.,Le, P.,Li, Q.,Lingardo, L.,Liu, W.,West Lu, M.,Mctigue, M.A.,Palmer, C.L.,Richardson, P.F.,Sach, N.W.,Smeal, T.,Smith, G.L.,Stewart, A.E.,Timofeevski, S.L.,Tsaparikos, K.,Wang, H.,Zhu, H.,Zhu, J.,Zou, H.Y.,Edwards, M.
The Design of Potent and Selective Inhibitors to Overcome Clinical Alk 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 (2.23 Å)