Discovery of SMD-3236: A Potent, Highly Selective and Efficacious SMARCA2 Degrader for the Treatment of SMARC4-Deficient Human Cancers.

SMARCA2 is an attractive synthetic lethal target in human cancers with mutated, inactivated SMARCA4. We report herein the discovery of highly potent and selective SMARCA2 PROTAC degraders, as exemplified by SMD-3236, which was designed using a new, high-affinity SMARCA ligand and a potent VHL-1 ligand. SMD-3236 achieves DC < 1 nM and > 95% against SMARCA2 and >2000-fold degradation selectivity over SMARCA4.

Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders.

In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands.

Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader.

STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with = 3.5 μM binding affinity, we obtained AK-068 with = 6 nM to STAT6 and at least >85-fold binding selectivity over STAT5.

Comprehensive Analyses of the Effects of the Small-Molecule Inhibitor of the UHM Domain in the Splicing Factor in Leukemia Cells.

Mutations in RNA splicing factor genes including , , and have been reported to contribute to development of myeloid neoplasms including myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML). Chemical tools targeting cells carrying these mutant genes remain limited and underdeveloped. Among the four proteins, mutant U2AF1 (U2AF1) acquires an altered 3' splice site selection preference and co-operates with the wild-type U2AF1 (U2AF1) to change various gene isoform patterns to support MDS cells survival and proliferation.