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Merck

The splicing modulator sulfonamide indisulam reduces AR-V7 in prostate cancer cells.

Bioorganic & medicinal chemistry (2020-10-18)
James E Melnyk, Veronica Steri, Hao G Nguyen, Byron Hann, Felix Y Feng, Kevan M Shokat
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.

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Mercury(II) amidochloride, ≥95.0%, powder
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