Total Synthesis and Chemoproteomics Connect Curcusone Diterpenes with Oncogenic Protein BRAT1

Abstract

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.

Total Synthesis of Natural Products using Gold Catalysis

“…curcusones exhibit a wide range of therapeutic applications [81] . They have been documented to display anti‐cancer cell proliferation and anti‐invasive activity [82,83] . Curcusone I and J were first isolated in 2013 by Lui et al.…”

“…[81] They have been documented to display anticancer cell proliferation and anti-invasive activity. [82,83] Curcusone I and J were first isolated in 2013 by Lui et al from the roots of Jatropha curcas. [84] However, the first total synthesis of curcusone I and J via gold catalysis was documented in 2017.…”

ICBS 2021: Looking Toward the Next Decade of Chemical Biology

“…15 The session was closed by Brendan Dwyer (The Scripps Research Institute), who described the total synthesis of naturally occurring anticancer curcusones. Through the synthesis of alkyne tagged analogues, and a biotin tagging/streptavidin enrichment strategy, they identified the "difficult to drug" oncoprotein BRAT1 as the target of the curcusones, 16 as well as an undisclosed E3 ligase, which is involved in mitochondrial dynamics and apoptosis, whose promise as a new E3 ligase for PROTAC development was demonstrated.…”