Abstract 2156: IK-930 is a novel TEAD inhibitor for the treatment of cancers harboring mutations in the Hippo signal transduction pathway

The Hippo pathway is critical to cancer progression, biogenesis, metastasis, and therapeutic resistance. Many cancer indications have a high frequency of mutations in the Hippo pathway. These pro-tumor mutations lead to constitutive TEAD transcription factor activation, which drives gene expression involved in cell growth and pro-survival signaling. To target cancers harboring mutations in the Hippo pathway, we have discovered and are developing IK-930, a novel small molecule that selectively inhibits TEAD-dependent transcription by directly blocking autopalmitoylation. IK-930 prevents this critical post-translational modification that is required for the functional interaction of TEAD with two transcriptional activators, YAP1 and TAZ (WWTR1). IK-930 inhibits in vitro proliferation of Hippo pathway-deficient cancer cell lines, but not Hippo pathway wild type cells. In human mesothelioma xenografts, IK-930 downregulates TEAD-dependent genes. Daily oral administration of IK-930 resulted in antitumor activity in Hippo-dysregulated mesothelioma xenograft models. In EGFR or KRAS mutated tumors, IK-930 enhanced apoptosis and in vivo antitumor activity in combination with EGFR and MEK inhibitors, respectively. IK-930 is inactive in a broad panel of kinases, receptors, and transporters, furthering evidence of selectivity. Multispecies pharmacokinetic analysis and additional in vitro ADME properties imply favorable pharmacokinetic properties, with a low potential for clinically significant drug-drug interactions. To identify indications that may be dependent on TEAD we evaluated tumor types for the incidence of gene alterations in the Hippo pathway, as well as for YAP1 and TAZ activation. YAP1 and TAZ activation was assessed by evaluating nuclear protein expression in tumor tissue microarrays. These analyses showed high YAP1 nuclear expression in tumors with frequent genetic alterations, that may help guide the development of IK-930. Mesothelioma ranks top among tumor types evaluated, due to high prevalence of YAP1 nuclear expression and Hippo pathway genetic alterations, which are predominantly mutations and copy number alterations in the tumor suppressor NF2. In summary, Hippo pathway dysregulation has been implicated in the etiology of multiple tumor types, including mesothelioma. IK-930 is a selective and potent TEAD inhibitor expected to enter the clinic in early 2022. Our analysis pointed to tumors with genetic alterations driving aberrant Hippo signaling. IK