SMARCA2 degrader-17

SMARCA2 degrader-17 is a degrader of SMARCA2, exhibiting synergistic antiproliferative effects with Adagrasib in cancer cells and capable of inhibiting tumor growth.

SMARCA2:0.72 nM (DC50), SMARCA4:14 nM (DC50)

SMARCA2 degrader-17 selectively induces polyubiquitination of wild-type SMARCA2 BD relative to SMARCA4 BD; SMARCA2-specific lysine residues K1405 and K1445, as well as the extension loop region unique to SMARCA2 BD, play a key role in this process [1].
SMARCA2 degrader-17 (0.1–1000 nM; 5–7 days for cell viability assays, 18–21 days for clonogenic assays) selectively inhibits the proliferation and colony formation of SMARCA4-deficient cancer cells, induces G1 phase cell cycle arrest, and upregulates p21 expression, while having no significant effect on SMARCA4 wild-type cells [1].
SMARCA2 degrader-17 potently and selectively degrades SMARCA2 in HeLa cells, with a DC50 of 0.72 nM (94% Dmax%) and a selectivity of 19-fold relative to SMARCA4 [2].
SMARCA2 degrader-17 (0.1–1000 nM) selectively inhibits the proliferation of SMARCA4-deficient/ knockout (KO) cancer cell lines (NCI-H1693, NCI-H838, HT1080 SM4 KO), while having no effect on SMARCA4 wild-type (WT) cancer cell lines; this result was determined by clonogenic assays [2].
SMARCA2 degrader-17 (50 nM) completely degrades SMARCA2 in SMARCA4-deficient NCI-H1693 cells and induces the dissociation of specific SWI/SNF complex subunits while maintaining the integrity of the core DNA finger-like complex [2].
SMARCA2 degrader-17 (50 nM; 72 h) alters gene expression in SMARCA4-deficient NCI-H1693 cells, downregulating oncogenes and cell cycle-related genes while upregulating immunogenicity-related genes, with a total of 600 differentially expressed genes [2].

SMARCA2 degrader-17 (100 mg/kg; subcutaneous injection; once every 3 days (Q3D)) induced significant tumor regression in the SMARCA4-mutant NCI-H1793 xenograft model [1].
SMARCA2 degrader-17 (100 mg/kg; subcutaneous injection; once weekly) induces potent tumor growth inhibition in the SMARCA4G12C-mutant CTG-0493 esophageal PDX model [1].
SMARCA2 degrader-17 (100 mg/kg; subcutaneous injection; once every 3 days (Q3D)) induces potent tumor growth inhibition in the NCI-H838 xenograft model and significantly degrades the target SMARCA2 (reduction >90%) [1].
SMARCA2 degrader-17 (200 mg/kg; subcutaneous injection; once every 3 days (Q3D)) induces significant tumor regression in the SMARCA4G12C-mutant LU11760 non-small cell lung cancer (NSCLC) PDX model [1].
SMARCA2 degrader-17 (200 mg/kg; subcutaneous injection; once every 3 days (Q3D)) induces significant tumor growth inhibition in the CTG-3710 NSCLC PDX model and Results: in near-complete downregulation of SMARCA2 (IHC H-score <10) [1].
SMARCA2 degrader-17 (administered on days 1, 4, and 7) induces potent, selective degradation of the SMARCA2 protein in PBMCs from healthy rats following administration on days 1, 4, and 7 [2].