YDR1 is potent, selective, and orally bioavailable SMARCA2 degrading PROTAC with DC50 of 6.3 nM (H322 cell ine), Dmax=99.4%, selectively inhibit gowth of SMARCA4 mutant lung cancer cell lines.
YDR1 potently degrades SMARCA2 in H322, HCC515, H2030, and H2126 cell lines with DC50 of 6.4 nM, 10.6 nM, 12.7 nM and 1.2 nM respectively, while achieving profound maximal degradation (Dmax) of 99.2%, 99.4%, 98.7% and 99.6% respectively.
YDR1 induces degradation of SMARCA2 in the classically accepted PROTAC fashion by E3 ligase-target protein-PROTAC ternary complex formation, ubiquitination, and via the proteasome.
YDR1 dose-dependently inhibits SMARCA4 mutant cell lines (H1568 and H1693) with average cellular IC50 of 78 nM respectively in clonogenic assays, with minimal impact on the growth of SMARCA4 WT cell lines.
YDR1 (40m/kg, oral gavage daily) moderately inhibited tumor growth in SMARCA4 mutant xenograft models of lung cancer.
YDR1 synergizes with sotorasib to inhibit growth of sotorasib-resistant KRASG12and SMARCA4 comutant cancer cells.