Dataset Information

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

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.

SUBMITTER: Pan P

PROVIDER: S-EPMC5704298 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Publications

Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type-I<sup>1/2</sup> Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation.

Pan Peichen P Yu Huidong H Liu Qinglan Q Kong Xiaotian X Chen Hu H Chen Jiean J Liu Qi Q Li Dan D Kang Yu Y Sun Huiyong H Zhou Wenfang W Tian Sheng S Cui Sunliang S Zhu Feng F Li Youyong Y Huang Yong Y Hou Tingjun T

ACS central science 20171103 11

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" ...[more]

PMID: 29202023

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Dataset Information

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

Publications

Combating Drug-Resistant Mutants of Anaplastic Lymphoma Kinase with Potent and Selective Type-I<sup>1/2</sup> Inhibitors by Stabilizing Unique DFG-Shifted Loop Conformation.

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