MS0621 (UNC0621, MS 0621) is a small-molecule modulator of EWSR1::FLI1-mediated chromatin, reverses EWSR1::FLI1-mediated chromatin accessibility, persistently and selectively inhibits cell proliferation in Ewing sarcoma cell lines (SK-N-MC, IC50=128 nM).
MS0621 displays no activity against clear cell sarcoma cell line with the oncogenic EWS::ATF1 rearrangement (SU-CCS-1), and two primary cell lines that either express FLI1 (HUVEC) or do not express FLI1 (RPTEC).
MS0621 induces a G1/S arrest in Ewing sarcoma cell lines.
MS0621 interacts with a core complex of proteins that includes hnRNPH1, EWSR1, BRG1, and EWSR1::FLI1 in the absence of RNA or intact chromatin.
hnRNPH1 knockdown recapitulates the effect of MS0621 on Ewing sarcoma cell proliferation.
MS0621 affects EWSR1::FLI1-mediated gene expression and alternative splicing.
MS0621 treatment recapitulated the effects of EWSR1::FLI1 loss on FAIRE, cell cycle, and gene expression through a mechanism independent of regulating EWSR1::FLI1 gene expression.
MS0621 decreases FAIRE signal at EWSR1::FLI1-bound loci without displacing the oncoprotein from chromatin.