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Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1

preprint
submitted on 23.11.2020, 02:38 and posted on 23.11.2020, 13:22 by Chengsen Cui, Brendan G. Dwyer, Chang Liu, Daniel Abegg, Zhongjian Cai, Dominic Hoch, Xianglin Yin, Nan Qiu, Jieqing Liu, Alexander Adibekian, Mingji Dai
Natural products are an indispensable source of lifesaving medicine, but natural product-based drug discovery often suffers from scarce natural supply and unknown mode of action. The study and development of anticancer curcusone diterpenes fall into such a dilemma. Meanwhile, many biologically-validated disease targets are considered “undruggable” due to the lack of enzymatic activity and/or predicted small molecule binding sites. The oncogenic BRCA1-associated ATM activator 1 (BRAT1) belongs to such an “undruggable” category. Here, we report our synthetic and chemoproteomics studies of the curcusone diterpenes that culminate in an efficient total synthesis and the identification of BRAT1 as a cellular target. We demonstrate for the first time that BRAT1 can be inhibited by a small molecule (curcusone D), resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown.

Funding

NIH R35 GM128570

NIH P30CA023168

History

Email Address of Submitting Author

mjdai@purdue.edu

Institution

Purdue University

Country

United States

ORCID For Submitting Author

0000-0001-7956-6426

Declaration of Conflict of Interest

M.D., A.A., C.C., B.G.D., Z.C. are inventors on patent application U.S. 63/084,594 submitted by Purdue University that covers the synthesis of curcusone derivatives.

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