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

Harshani R. Lawrence, Kiran Mahajan, Yunting Luo, Daniel Zhang, Nathan Tindall, Miles Huseyin, Harsukh Gevariya, Sakib Kazi, Sevil Ozcan, Nupam P. Mahajan, Nicholas J. Lawrence

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17 Scopus citations

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 33P 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, 33P 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 (t1/2 > 6 h).

Original languageEnglish
Pages (from-to)2746-2763
Number of pages18
JournalJournal of Medicinal Chemistry
Volume58
Issue number6
DOIs
StatePublished - Mar 26 2015
Externally publishedYes

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    Lawrence, H. R., Mahajan, K., Luo, Y., Zhang, D., Tindall, N., Huseyin, M., Gevariya, H., Kazi, S., Ozcan, S., Mahajan, N. P., & Lawrence, N. J. (2015). Development of novel ACK1/TNK2 inhibitors using a fragment-based approach. Journal of Medicinal Chemistry, 58(6), 2746-2763. https://doi.org/10.1021/jm501929n