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J Med Chem. 2015 Mar 26;58(6):2746-63. doi: 10.1021/jm501929n. Epub 2015 Mar 17.

Development of novel ACK1/TNK2 inhibitors using a fragment-based approach.

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1
§Department of Oncologic Sciences, University of South Florida, Tampa, Florida 33620, United States.

Abstract

The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process. The hybrid library was screened by enzyme-linked immunosorbent assay-based kinase inhibition and (33)P HotSpot assays. Systematic structure-activity relationship studies led to the identification of compound (R)-9b, which shows potent in vitro (IC50 = 56 nM, n = 3, (33)P HotSpot assay) and in vivo (IC50 < 2 μM, human cancer cell lines) ACK1 inhibition. Both (R)-9b and (S)-9b were stable in human plasma and displayed a long half-life (t(1/2) > 6 h).

PMID:
25699576
PMCID:
PMC4605435
DOI:
10.1021/jm501929n
[Indexed for MEDLINE]
Free PMC Article

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