5AAB

Structure of C1156Y,L1198F Mutant Human Anaplastic Lymphoma Kinase in Complex with Crizotinib

5AAB の概要

• エントリーDOI: 10.2210/pdb5aab/pdb
• 関連するPDBエントリー: 5A9U 5AA8 5AA9 5AAA 5AAC
• 分子名称: ALK TYROSINE 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)
• 機能のキーワード: transferase, receptor tyrosine kinase, anaplastic lymphoma kinase, inhibitor, mutant
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37453.74

構造登録者

McTigue, M.,Deng, Y.,Liu, W.,Brooun, A.,Stewart, A. (登録日: 2015-07-23, 公開日: 2016-06-08, 最終更新日: 2024-01-10)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.2 Å)