4ANL

Structure of G1269A Mutant Anaplastic Lymphoma Kinase

Summary for 4ANL

• Entry DOI: 10.2210/pdb4anl/pdb
• Related: 4ANQ 4ANS 4AOI
• Descriptor: ALK TYROSINE KINASE RECEPTOR (2 entities in total)
• Functional Keywords: transferase, crizotinib
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 38610.15

Authors

McTigue, M.,Deng, Y.,Liu, W.,Brooun, A. (deposition date: 2012-03-20, release date: 2013-03-27, 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)