The Hippo pathway is an important regulator of cell proliferation and one of the last major oncogenic pathways not yet extensively targeted in precision oncology. The Hippo pathway is executed by the YAP1/TAZ (WWTR1) co-activators and the TEAD family of transcription factors, which consists of four paralogs (TEAD1-4) with both redundant and unique functions. The transcriptional targets of TEADs include genes playing tumor-promoting roles, including pro-proliferative, immunosuppressive, and anti-apoptotic genes. A growing body of research points to the central importance of the Hippo pathway as a key driver of oncogenesis and as key resistance mechanism to inhibitors of the MAPK pathway or its upstream activators, such as receptor tyrosine kinases. Sporos BioDiscovery has developed novel inhibitors that reversibly bind to the palmitoylation site of TEAD transcription factors to block Hippo pathway activity. Sporos BioDiscovery’s internal bioinformatic insights were leveraged to fine tune the inhibitory activity against the four TEAD paralogs, to maximize efficacy and minimize toxicity. Key characteristics of the SPR1 TEAD inhibitors: (i) low nM, single-agent activity against multiple TEAD-dependent cell lines in vitro in established Hippo-pathway hyperactive mesothelioma cell lines as well as in several non-mesothelioma, cell lines without any obvious lesions in the upstream components of the Hippo pathway. (ii) activity against multiple tumor models in vivo with tumor regression observed even in large established tumors, a feat not previously reported with any other TEAD inhibitor. (iii) strong interactions with inhibitors of the MAPK pathway and inhibitors of its upstream activators, such as RTKs. (iv) favorable ADME profile in rodents, dogs and NHPs, as well as a favorable safety profile. In sum, SPR1 presents monotherapy opportunities in ultra-responder populations based on internal bioinformatic insights, while broader potential exists as an adjuvant for precision oncology targeted therapies, particularly within the MAPK pathway and its upstream activators.

Citation Format: Florian Muller, Erkan Baloglu, Andrew D. Morley, Deepavali Chakravarti, Selvi Kunnimalaiyaan, Jeno Gyruis, Sharon Shacham. A next generation TEAD inhibitor with refined isoform specificity for superior safety & efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 445.