5AA9

Structure of L1198F Mutant Human Anaplastic Lymphoma Kinase in Complex with PF-06463922 ((10R)-7-amino-12-fluoro-2,10,16-trimethyl- 15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo(4,3-h)(2,5,11) benzoxadiazacyclotetradecine-3-carbonitrile).

Summary for 5AA9

• Entry DOI: 10.2210/pdb5aa9/pdb
• Related: 5A9U 5AA8 5AAA 5AAB 5AAC
• Descriptor: ALK TYROSINE KINASE RECEPTOR, (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile (3 entities in total)
• Functional Keywords: transferase, receptor tyrosine kinase, inhibitor, mutant
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 37349.78

Authors

McTigue, M.,Deng, Y.-L.,Liu, W.,Brooun, A.,Stewart, A. (deposition date: 2015-07-23, release date: 2016-06-08, Last modification date: 2024-01-10)

Primary citation

Shaw, A.T.,Friboulet, L.,Leshchiner, I.,Gainor, J.F.,Bergqvist, S.,Brooun, A.,Burke, B.J.,Deng, Y.,Liu, W.,Dardaei, L.,Frias, R.L.,Schultz, K.R.,Logan, J.,James, L.P.,Smeal, T.,Timofeevski, S.,Katayama, R.,Iafrate, A.J.,Le, L.,Mctigue, M.,Getz, G.,Johnson, T.W.,Engelman, J.A.
Resensitization to Crizotinib by the Lorlatinib Alk Resistance Mutation L1198F.
N.Engl.J.Med., 374:54-, 2016

PubMed Abstract: In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).

PubMed: 26698910
DOI: 10.1056/NEJMOA1508887

Experimental method

X-RAY DIFFRACTION (1.93 Å)