Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors
Name
Lauffenburger_Studies of TAK.pdf
Description
Accepted version
Size
1.21 MB
Format
Adobe PDF
Checksum (MD5)
67ce9d10f7ef6dfaafec2a13487971a6
Author(s)
Tan, Li
Gurbani, Deepak
Weisberg, Ellen L.
Jones II, Douglas S.
Rao, Suman
Singer, William D.
Bernard, Faviola M.
Mowafy, Samar
Jenney, Annie
Du, Guangyan
Date Issued
February 2017
Journal
Bioorganic & Medicinal Chemistry
Publisher
Elsevier BV
Citation
Tan, Li et al. "Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors." Bioorganic & Medicinal Chemistry 25, 4 (Febraury 2017): 1320-1328. © 2016 Elsevier Ltd
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.bmc.2016.11.034
