LAUSR

The Hippo pathway is an evolutionarily conserved signaling cascade. Its dysregulation may lead to cancer progression, metastasis, cancer therapy resistance, and immune evasion. Diverse genetic aberrations leading to YAP/TAZ hyperactivation have been elucidated over the last 20 years. Almost all the pro-tumor mutations lead to constitutive TEAD transcription factor activation, suggesting that targeting TEAD transcription factors could offer an important therapeutic opportunity. Employing structure-based drug design, we have discovered GH658, a novel allosteric TEAD inhibitor that selectively targets the auto-palmitoylation pocket of TEAD proteins. In vitro, GH658 displayed a low nM potency in TEAD-based reporter assays, which translated to specific low nM inhibition of NF2 deficient mesothelioma proliferation. In vivo, GH658 demonstrated favorable pharmacokinetic properties in different species and showed acceptable safety profile. Furthermore, daily oral dosing of GH658 led to complete growth inhibition of NF2 mutant xenograft tumors without adverse effect on body weight. More importantly, GH658 displayed significant in vivo effect on drug tolerant persistent cancer cells and drug resistance against inhibitors targeting EGFR‒RAS signaling pathways in combination studies. In summary, with potent in vitro and in vivo efficacy of targeting YAP/TAZ‒TEAD transcriptional complex, GH658 not only showed consistent monotherapy activity in selected cancer models, but also demonstrated significant synergistic effects in diverse drug combination studies. Citation Format: Jie Jack Li, Guiping Zhang, Jiapeng Li. Discovery of GH658, a novel tead allosteric inhibitor as a cancer therapy [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 3401.