YD54 is potent, selective, and orally bioavailable SMARCA2 degrading PROTAC with DC50 of 1.2 nM (H322 cell ine), Dmax=99.3%, selectively inhibit gowth of SMARCA4 mutant lung cancer cell lines.
YD54 degrades SMARCA2 in H1792 cells with DC50 of 8.1 nM at 24 h and 16 nM at 48 h, with a Dmax of 98.9% at 24 h and 99.2% at 48 h.
YD54 potently degrades SMARCA2 in H322, HCC515, H2030, and H2126 cell lines with DC50 of 1 nM, 1.2 nM, 10.3 nM and 1.6 nM respectively while achieving a maximal degradation (Dmax) of 99.3%, 98.9%, 98.6% and 98.9%.
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.
YD54 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.
YD54 (5 mg/kg, once daily by oral gavage for 19 days) inhibits tumor growth with a tumor growth inhibition (TGI) of 62.5, 48.8, and 93.4% in H2023, HCC515, and H2030 xenografts, respectively。
YD54 synergizes with sotorasib to inhibit growth of sotorasib-resistant KRASG12and SMARCA4 comutant cancer cells.