Abstract 5913: TEAD1/4 inhibitors exhibit deeper biological impact and broader activity compared to TEAD1-only inhibitors in both monotherapy and combination without additional kidney toxicity

Abstract

Abstract The TEAD transcription factors in association with the YAP/TAZ co-activators drive the expression of pro-proliferative and pro-oncogenic genes that underlies the transformed phenotype of many carcinomas. In addition, YAP-TEAD transcriptional activity is emerging as a major resistance mechanism for diverse precision oncology drugs, with the most extensive data for resistance to drugs targeting the MAPK pathway. There is a strong interest in generating inhibitors of YAP/TEAD transcriptional activity with TEAD palmitic acid site inhibitors having demonstrated encouraging pre-clinical activity and now clinical activity with confirmed objective responses with the TEAD1/2/3 inhibitor VT3989. However, the TEAD1-preferential inhibitor IK930 did not yield any objective responses but also showed a more favorable safety profile especially with respect to proteinuria. These contrasting clinical read-outs provide a good lead-in to a critical design challenge/question of TEAD palmitic acid site inhibitors: the optimization of inhibitory profile against the respective four TEAD paralogs (TEAD1-4). In depth bioinformatic analyses led Sporos investigators to conclude that while TEAD1 inhibition was a minimum requirement for anti-neoplastic activity, inhibition of other paralogs would be necessary for maximizing biological impact and a TEAD1/4 inhibitor would provide the best balance of anti-neoplastic activity and toxicity. Activity against TEAD2 was identified as counter-productive associated with a context-specific paradoxical stimulation of cell proliferation and tumor growth while activity against TEAD3 was flagged as a major driver of podocyte effacement and kidney toxicity. Here, we provide novel corroborating data supporting this selection of inhibitory profile. We provide an update on the pre-clinical efficacy and toxicology of SPR1, Sporos’s TEAD1/4 preferential inhibitor which favorably contrasts with other TEAD inhibitors such as the TEAD1/3/4 inhibitor VT3989 and the TEAD1 inhibitor VT103 and IK930 in both the monotherapy and combination setting. We show that 1) SPR1 displays broader and deeper cell-based activity and extends the utility of TEAD inhibitors outside of mesothelioma and NF2 mutants 2) SPR1 shows stronger activity than TEAD1-only inhibitors in combination with MAPK and EGFR inhibitors in vitro and in vivo 3) SPR1 does not cause proteinuria in mice; dogs or rats even above therapeutic doses 4) SPR1 does not show the context-specific stimulation of tumor growth in Lung PDX previously observed with VT3989 and other inhibitors that include TEAD2 in their profile. Taken together - the data suggests SPR1 is positioned to become a best-in-class TEAD palmitic acid site inhibitor with broad utility in both monotherapy and combination setting. Citation Format: Florian Muller, Selvi Kunnimalaiyaan, Parth Mangrolia, Jill Olson. TEAD1/4 inhibitors exhibit deeper biological impact and broader activity compared to TEAD1-only inhibitors in both monotherapy and combination without additional kidney toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5913.