AZ4331 (AZ'4331) is a potent, covalent pan-TEAD palmitoylation inhibitor, exhibits target engagement in the TEAD central pocket with IC50 of 381 nM, 20 nM, 14 nM and 31 nM for TEAD1, TEAD2, TEAD3 and TEAD4 in biochemical TEAD-TR-FRET assays, inhibits YAP-TEAD binding and TEAD-dependent transcription.
AZ4331 (AZ'4331) induces dose-dependent reduction in palmitoylated TEAD1-4 in FLAG-tagged TEAD proteins in LATS1/2-deleted MSTO-211H mesothelioma cells.
AZ4331 (AZ'4331) resulted in a marked loss of TEAD-bound YAP (IC50 = 9.6 nM) in NF2-deleted NCI-H226 cells.
AZ4331 (AZ'4331) treatment reduced TEAD luciferase reporter expression (IC50 = 20 nM).
AZ4331 (AZ'4331) caused a dose dependent reduction in the expression of canonical, TEAD-dependent target genes including CYR61, CTGF, and ANKRD1, while not affecting YAP1 mRNA expression, in NCI-H226 cells.
AZ4331 (AZ'4331) reduced the proliferation of NCI-H226 cells in vitro (GI50 = 92 nM) while not affecting the growth rate of NF2-wildtype NCI-H2452 cells (GI50 = >18 µM), reduced proliferation of Hippo pathway-altered mesothelioma in vitro.
AZ4331 (AZ'4331) (10-100 mg/kg, PO QD) drives tumor regression in NF2-deleted NCI-H226 mesothelioma xenografts.
AZ4331 (AZ'4331) provides combination benefit in NSCLC with the EGFR inhibitor osimertinib in vitro and in vivo.