SD-436 is a highly potent and selective STAT3 PROTAC degrader with DC50 of 10 nM and Dmax >95% in SU-DHL-1 lymphoma cell line.
SD-436 at 10 mg/kg depleted STAT3 protein by ∼90% in both spleen and liver tissues at both 48 and 72 h time-points in mice.
SD-436 potently inhibited cell growth in the MOLM-16 leukemia cell line, as well as in the SU-DHL-1 and SUP-M2 lymphoma cell lines with highly activated STAT3 (IC50=4-40 nM).
SD-436 effectively reduced the levels of the mutated STAT3 protein in a dose-dependent manner.
SD-436 demonstrated a DC50 value of 2.5 nM and reduced the mutated STAT3 protein by >90% at 64 nM, in Pfeiffer cell line, which carries the STAT3K658R mutation.
SD-436 shows no or minimal effect on the levels STAT1, STAT2, and STAT5 proteins at concentrations up to 40 μM.
SD-436 binds to STAT3 with a higher affinity than SD-36 and displays 14-19 fold selectivity for STAT3 over STAT1 and STAT4 proteins.
A single intravenous administration of SD-436 at 5 mg/kg effectively induces rapid, complete, and durable depletion of STAT3 in mouse native and xenograft tumor tissues.
SD-436 achieves complete and long-lasting tumor regression even with a weekly dosing schedule in leukemia and lymphoma xenograft models in mice.