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Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1

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.


NIH R35 GM128570

NIH P30CA023168


Email Address of Submitting Author


Purdue University


United States

ORCID For Submitting Author


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.