YSA64

YSA64 is an orally active RBM39 -targeting molecular glue. YSA64 promotes degradation via formation of a DCAF15 / DDB1 ternary complex, dependent on Cullin-RING E3 ligase and proteasome activity. YSA64 can be used for the research of acute myeloid leukemia and Ewing sarcoma ^[1].

In Vivo, YSA64 (Compound 41) (100-200 mg/kg; p.o.; once daily; 10 days) exhibits significant in vivo antitumor efficacy in MV4-11 xenograft models, achieving up to 51.9% tumor growth inhibition, with a favorable safety profile and no observed weight loss^[1].

In Vitro, YSA64 (Compound 41) (4 days) potently inhibits HCT-116 colorectal cancer cell proliferation with an IC₅₀ of 166 nM^[1]. YSA64 (0.05-0.8 μM; 24 h) induces robust degradation of RBM39 in HCT-116 colorectal cancer cells^[1]. YSA64 (4 days) inhibits proliferation of multiple cancer cell lines with varying potency, showing highest activity in A673 Ewing sarcoma (IC₅₀ = 125.3 nM) and MV4-11 acute myeloid leukemia (IC₅₀ = 111.7 nM) cells^[1]. YSA64 (24 h) induces robust degradation of RBM39 and CEP192 in A673 Ewing sarcoma cells^[1]. YSA64-induced RBM39 degradation in A673 Ewing sarcoma cells requires intact proteasome and Cullin-RING E3 ligase activity^[1]. YSA64 (24 h) induces dose-dependent degradation of RBM39 and CEP192 in MV4-11 acute myeloid leukemia cells following 24 h incubation, with RBM39 degradation potency comparable to E7820^[1].

References:
[1]. Lyu X, et al. Discovery and characterization of YSA64, a RBM39 degrader with in vivo efficacy and potent cellular activity in pediatric Ewing sarcoma A673. Eur J Med Chem. 2026;314:118921.