Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors

Li Tan; Suman Rao; Samar Mowafy; Guangyan Du; Nathanael S. Gray; Deepak Gurbani; Ellen L. Weisberg; Douglas S. Jones; William D. Singer; Faviola M. Bernard; Annie Jenney; Atsushi Nonami; James D. Griffin; Douglas A. Lauffenburger; Kenneth D. Westover; Peter K. Sorger

doi:10.1016/j.bmc.2016.11.034

Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors

Li Tan, Suman Rao, Samar Mowafy, Guangyan Du, Nathanael S. Gray, Deepak Gurbani, Ellen L. Weisberg, Douglas S. Jones, William D. Singer, Faviola M. Bernard, Annie Jenney, Atsushi Nonami, James D. Griffin, Douglas A. Lauffenburger, Kenneth D. Westover, Peter K. Sorger

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

Abstract

Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.

Original language	English (US)
Pages (from-to)	1320-1328
Number of pages	9
Journal	Bioorganic and Medicinal Chemistry
Volume	25
Issue number	4
DOIs	https://doi.org/10.1016/j.bmc.2016.11.034
State	Published - 2017

Keywords

Cancer
Cytokine secretion
Multitarget
Polypharmacology
TAK1

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2016.11.034

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Tan, L., Rao, S., Mowafy, S., Du, G., Gray, N. S., Gurbani, D., Weisberg, E. L., Jones, D. S., Singer, W. D., Bernard, F. M., Jenney, A., Nonami, A., Griffin, J. D., Lauffenburger, D. A., Westover, K. D., & Sorger, P. K. (2017). Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. Bioorganic and Medicinal Chemistry, 25(4), 1320-1328. https://doi.org/10.1016/j.bmc.2016.11.034

Tan, L, Rao, S, Mowafy, S, Du, G, Gray, NS, Gurbani, D, Weisberg, EL, Jones, DS, Singer, WD, Bernard, FM, Jenney, A, Nonami, A, Griffin, JD, Lauffenburger, DA, Westover, KD & Sorger, PK 2017, 'Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors', Bioorganic and Medicinal Chemistry, vol. 25, no. 4, pp. 1320-1328. https://doi.org/10.1016/j.bmc.2016.11.034

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abstract = "Targeted polypharmacology provides an efficient method of treating diseases such as cancer with complex, multigenic causes provided that compounds with advantageous activity profiles can be discovered. Novel covalent TAK1 inhibitors were validated in cellular contexts for their ability to inhibit the TAK1 kinase and for their polypharmacology. Several inhibitors phenocopied reported TAK1 inhibitor 5Z-7-oxozaenol with comparable efficacy and complementary kinase selectivity profiles. Compound 5 exhibited the greatest potency in RAS-mutated and wild-type RAS cell lines from various cancer types. A biotinylated derivative of 5, 27, was used to verify TAK1 binding in cells. The newly described inhibitors constitute useful tools for further development of multi-targeting TAK1-centered inhibitors for cancer and other diseases.",

keywords = "Cancer, Cytokine secretion, Multitarget, Polypharmacology, TAK1",

author = "Li Tan and Suman Rao and Samar Mowafy and Guangyan Du and Gray, {Nathanael S.} and Deepak Gurbani and Weisberg, {Ellen L.} and Jones, {Douglas S.} and Singer, {William D.} and Bernard, {Faviola M.} and Annie Jenney and Atsushi Nonami and Griffin, {James D.} and Lauffenburger, {Douglas A.} and Westover, {Kenneth D.} and Sorger, {Peter K.}",

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year = "2017",

doi = "10.1016/j.bmc.2016.11.034",

language = "English (US)",

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AU - Gurbani, Deepak

AU - Weisberg, Ellen L.

AU - Jones, Douglas S.

AU - Singer, William D.

AU - Bernard, Faviola M.

AU - Jenney, Annie

AU - Nonami, Atsushi

AU - Griffin, James D.

AU - Lauffenburger, Douglas A.

AU - Westover, Kenneth D.

AU - Sorger, Peter K.

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KW - Cytokine secretion

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Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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