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ACS Cent Sci. 2017 Nov 22;3(11):1208-1220. doi: 10.1021/acscentsci.7b00419. Epub 2017 Nov 3.

Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type-I1/2 Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation.

Author information

1
College of Pharmaceutical Sciences and State Key Lab of CAD&CG, Zhejiang University, Hangzhou, Zhejiang 310058, China.
2
Rongene Pharma Co., Ltd., Shenzhen, Guandong 518054, China.
3
Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, Guangdong 518055, China.
4
Innovative Drug R & D Center, Shenzhen Salubris Pharmaceuticals Co., Ltd., Huabao Industrial Zone, Shenzhen 518102, China.
5
Institute of Functional Nano and Soft Materials (FUNSOM) and Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.

Abstract

Targeted inhibition of anaplastic lymphoma kinase (ALK) dramatically improved therapeutic outcomes in the treatment of ALK-positive cancers, but unfortunately patients invariably progressed due to acquired resistance mutations in ALK. Currently available drugs are all type-I inhibitors bound to the ATP-binding pocket and are most likely to be resistant in patients harboring genetic mutations surrounding the ATP pocket. To overcome drug resistance, we rationally designed a novel kind of "bridge" inhibitor, which specially bind into an extended hydrophobic back pocket adjacent to the ATP-binding site of ALK. The novel type-I1/2 inhibitors display excellent antiproliferation activity against ALK-positive cancer cells and appear superior to two clinically used drugs, crizotinib and ceritinib. Structural and molecular modeling analyses indicate that the inhibitor induces dramatic conformational transition and stabilizes unique DFG-shifted loop conformation, enabling persistent sensitivity to different genetic mutations in ALK. These data highlight a rationale for further development of next-generation ALK inhibitors to combat drug resistance.

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