OPN-9643 is a covalent inhibitor that targets the central palmitoyl-binding pocket of TEADs, with an IC50 of 15 nM. It prevents auto-palmitoylation and reduces TEAD-driven luciferase activity, as well as classic TEAD target genes such as CTGF and CYR61. OPN-9643 is applicable in cancer research, including studies on melanoma.

TEAD:15 nM

OPN-9643, at a concentration of 2 µM for 24-48 hours, reduces the expression of TEAD target genes (CTGF and CYR61) in SOX10 KO cells and decreases luciferase activity. Moreover, OPN-9643 lowers the expression of other known TEAD target genes such as DKK1, MYC, and TGF-β2 in SOX10 KO melanoma cells. When used in NCI-H226 cells for 5 days, OPN-9643 inhibits TEAD activity and cell proliferation with an IC50 of 123 nM. In combination with BRAFi (BRAF inhibitor) and MEKi (MEK inhibitor), it significantly reduces the growth of A375 SOX10 KO cells compared to OPN-9643 alone (2 μM; 48-72 hours). Additionally, OPN-9643 (2 μM; 48 hours) increases the levels of cleaved-PARP and cleaved-GSDME in co-treated SOX10 KO cells.