The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells. Issue 20 (15th October 2020)

• Record Type: Journal Article
• Authors: Melnyk, James E.; Steri, Veronica; Nguyen, Hao G.; Hann, Byron; Feng, Felix Y.; Shokat, Kevan M.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 20(2020)
• Publication Date: 2020-10-15
• Subjects: AR-V7 -- Indisulam -- Alternative splicing -- RBM39 -- Prostate cancer -- Androgen receptor; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115712
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Alternative splicing of the androgen receptor (AR) is frequently observed in castration resistant prostate cancer (CRPC). One AR isoform, the AR-V7 splice variant, is a constitutively active transcription factor which lacks a ligand binding domain and is therefore undruggable. AR-V7 expression correlates with resistance to androgen receptor signaling inhibitors (ARSi) and poor clinical prognoses. The occurrence of the AR-V7 splice variant is driven by alternative splicing of AR pre-mRNA by the spliceosome, however the mechanistic details are poorly understood. We demonstrate that the splicing factor RBM39 is critical for alternative splicing of the AR-V7 splice variant mRNA transcripts from AR pre-mRNA, and that the anti-cancer drug, indisulam, reduces AR-V7 mRNA levels by degrading RBM39. We report that indisulam effectively reduces AR-V7 in in vitro and in vivo models.