MS181 is a first-in-class CRBN-recruiting and EED-binding (Kd=190 nM) polycomb repressive complex 1 (PRC1) degrader, preferentially degrades PRC1 components BMI1 and RING1B over PRC2 components EZH2 and SUZ12.
MS181 causes preferential degradation of BMI1 and RING1B over EED with DC50 values of 1.7, 1.3, and 3.3 μM, respectively, in K562 myelogenous leukemia cell line.
MS181 shows no significant effect on the histone H3 lysine 27 trimethylation (H3K27me3) mark catalyzed by the PRC2 complex.
MS181 also does not induce the degradation of RYBP, YAF, and CBX8, which are noncanonical PRC1 components, at up to 10 μM in K562 cells while modestly degrading RING1A.
It is unclear how MS181 induces preferential polyubiquitination and degradation of BMI1 and RING1B over EED.
inhibits the proliferation in EZH2-insensitive and VHL-defective cancer cell lines with GI50 of 3.7 uM agianst K562 cells, effectively increases the mRNA levels of PRC1 target genes HoxA and HoxD.
MS181, but not MS147, degrades BMI1 and RING1B and inhibits cell growth in the VHL-defective 786-O RCC cell line.
MS181 degrades BMI1 and RING1B, reduces the H2AK119ub mark and suppresses the proliferation and colony formation in MDA-MB-468 cells.
MS181 is nontoxic in normal cells and bioavailable in mice.