STAT3 is a transcription factor that regulates many biological processes and has been implicated as a direct driver of multiple tumor types. STAT3 controls – among other processes – differentiation, survival, proliferation and angiogenesis, typically in response to growth factors and cytokines. Due to potency and selectivity challenges, STAT3 has traditionally been considered to lack an easily druggable pocket. We believe the preclinical data we have generated to date suggest the potential of STAT3 degraders to overcome these challenges.
Our STAT3 degrader discovery program has identified a lead compound, SD-436, that potently and rapidly degrades the target with high specificity with respect to degradation of other STAT proteins. SD-436 exhibits promising potency against wild type STAT3 in human peripheral blood mononuclear cells (PBMCs) as well as a mutated STAT3 protein (K658R) in the Pfeiffer cell line, with degradation achieved at low nM concentrations. In a leukemia xenograft tumor model with an activated STAT3 pathway, IV administration of SD-436 resulted in deep reductions in tumor volume. The lowest dose tested, 5 mg/kg weekly, achieved rapid and complete tumor regression.