Friday, May 28, 2021

Identification of a Covalent Importin-5 Inhibitor, Goyazensolide, from a Collective Synthesis of Furanoheliangolides

Weilong Liu, Rémi Patouret, Sofia Barluenga, Michael Plank, Robbie Loewith, and Nicolas Winssinger

ACS Central Science 2021
DOI: 10.1021/acscentsci.1c00056

Sesquiterpenes are a rich source of covalent inhibitors with a long history in traditional medicine and include several important therapeutics and tool compounds. Herein, we report the total synthesis of 16 sesquiterpene lactones via a build/couple/pair strategy, including goyasensolide. Using an alkyne-tagged cellular probe and proteomics analysis, we discovered that goyazensolide selectively targets the oncoprotein importin-5 (IPO5) for covalent engagement. We further demonstrate that goyazensolide inhibits the translocation of RASAL-2, a cargo of IPO5, into the nucleus and perturbs the binding between IPO5 and two specific viral nuclear localization sequences.

at

Glecirasib, a potent and selective covalent KRAS G12C inhibitor exhibiting synergism 2 with cetuximab or SHP2 inhibitor JAB-3312

Wang, P., Sun, X., He, X., Kang, D., Liu, X., Liu, D., Li, A., Yang, G., Lin, Y., Li, S., Wang, Y., & Wang, Y. Cancer research communica...