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.
journal_name
Eur J Med Chemjournal_title
European journal of medicinal chemistryauthors
Tu X,Chen X,Zhang D,Gao M,Liang J,Bao G,Zhang J,Peng S,Zhang X,Zeng Z,Su Ydoi
10.1016/j.ejmech.2020.113020subject
Has Abstractpub_date
2021-02-05 00:00:00pages
113020eissn
0223-5234issn
1768-3254pii
S0223-5234(20)30992-2journal_volume
211pub_type
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