Optimization of novel oxidative DIMs as Nur77 modulators of the Nur77-Bcl-2 apoptotic pathway.

Abstract	Nur77, an orphan nuclear receptor, is a member of the nuclear receptor superfamily. Nur77 plays important roles in various biological processes. Previously we reported that BI1071(DIM-C-pPhCF3+MeSO3-), an oxidized form and methanesulfonate salt of (4-CF3-Ph-C-DIM), can modulate Nur77's non-genomic apoptotic pathway through that Nur77 translocated from the nucleus to mitochondria to induce cytochrome c releasing and promote apoptosis of cancer cell. Here we report our efforts to further optimize BI1071. A series of BI1071 analogs were designed, synthesized and their apoptosis potency was systematically evaluated. Our preliminary structure-activity relationship study identified compound 10b as a better modulator with strong binding to Nur77 and enhanced apoptotic activity. Binding studies demonstrated that 10b could bind to its target Nur77 with an affinity value of 33 nM. Furthermore, mechanism studies reveal that 10b acts as an anticancer agent by utilizing the Nur77-Bcl-2 apoptotic pathway.
Authors	Xuhuang Tu, Xiaohui Chen, Dongliang Zhang, Meichun Gao, Jingmei Liang, Guoliang Bao, Jie Zhang, Shuangzhou Peng, Xiaokun Zhang, Zhiping Zeng, Ying Su
Journal	European journal of medicinal chemistry (Eur J Med Chem) Vol. 211 Pg. 113020 (Feb 05 2021) ISSN: 1768-3254 [Electronic] France
PMID	33279290 (Publication Type: Journal Article)
Copyright	Copyright © 2020 Elsevier Masson SAS. All rights reserved.
Chemical References	Antineoplastic Agents BCL2 protein, human NR4A1 protein, human Nuclear Receptor Subfamily 4, Group A, Member 1 Proto-Oncogene Proteins c-bcl-2
Topics	Animals Antineoplastic Agents (chemical synthesis, chemistry, pharmacology) Apoptosis (drug effects) Cell Proliferation (drug effects) Cells, Cultured Dose-Response Relationship, Drug Drug Screening Assays, Antitumor Female Humans Male Mice Mice, Transgenic Molecular Docking Simulation Molecular Structure Neoplasms, Experimental (drug therapy, metabolism, pathology) Nuclear Receptor Subfamily 4, Group A, Member 1 (metabolism) Oxidation-Reduction Proto-Oncogene Proteins c-bcl-2 (metabolism) Rats Rats, Sprague-Dawley Structure-Activity Relationship

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