MS41 is a potent and selective, VHL-recruiting ENL PROTAC degrader, induces robust ENL degradation in a variety of human leukemia cell lines with DC50 of 3.50, 2.84, 3.03, and 26.58 nM in MV4;11, SEMK2, Jurkat, and KASUMI1, respectively, Dmax>93%.
MS41 induces ENL protein degradation through the UPS.
MS41 exhibitscomparable binding affinities to ENL and AF9 YEATS domain, with no affinity GAS41 or YEATS2 YEATS domains (with IC50 > 50 μM).
MS41 efficiently degrades both ENL and AF9 in a concentration-dependent manner in cells, whereas has no effect on GAS41 and YEATS2 protein levels.
MS41 exhibits potent inhibition of leukemia cell survival, with IC50 of 21.28 and 25.06 nM against MV4;11 and RS4;11 cells, respectively.
MS41 also suppresses cell growth in leukemia cell lines harboring other MLL fusions, such as OCI-AML2 and ML-2 with MLL-AF6 fusions and NOMO-1 with MLL-AF9 fusion, as well as KASUMI1, a leukemia cell line harboring the AML1-ETO translocation.
MS41 suppresses ENL-dependent oncogenic gene expression programs, reduces chromatin occupancy of ENL-associated transcription elongation machinery.
MS41 (50 mg/kg) suppresses leukemia progression in a xenograft model of MLL-r leukemia, with negligible in vivo toxicity and a mild impact on normal hematopoiesis.