LAUSR

Pharmacological inhibitors of TEAD transcription factors have emerged as a promising novel class of anti-cancer agents. TEAD inhibitors disrupt oncogenic YAP/TAZ signaling, resulting in cell cycle arrest and cell death in susceptible cancers. In preclinical models, cancer cell lines with alterations in the Hippo signaling pathway, such as mutations or loss of NF2 or LATS, are particularly sensitive to inhibition of TEAD signaling. In addition, YAP/TAZ-TEAD signaling is thought to play a role in resistance to several targeted therapies, such as EGFR inhibitors and MEK inhibitors. BGI-9004 is a covalent inhibitor of TEAD1-4 with low nanomolar potency in a TEAD reporter cell line and anti-cancer activity in vitro and in vivo. In the NF2-deficient NCI-H226 and the NF2-wildtype, LATS-mutant MST-O211H mesothelioma xenograft models, BGI-9004 treatment resulted in sustained tumor regressions over a 28d treatment course. Anti-cancer activity was accompanied by significant inhibition of TEAD-mediated transcription in BGI-9004-treated tumors, and no adverse effects on the body weight of treated mice were observed. Moreover, proteome-wide protein binding of BGI-9004 was assessed by Isobaric Mass Tagged Affinity Characterization (IMTACTM), which confirmed its high selectivity for TEAD. In line with this, BGI-9004 had a clean profile in a panel of protein targets that present potential safety liabilities (CEREP safety panel). These findings prompted us to explore the combination potential of BGI-9004 with other targeted therapies, including inhibitors of EGFR, MEK and mutant KRASG12C. Here, we found that BGI-9004 potentiated the effect of other targeted therapies. In particular, we generated dose response matrices for BGI-9004 and inhibitors of KRASG12C and KRASG12D in several KRAS-mutant cell lines, including three lung cancer cell lines, and demonstrated synergy for the combination. These results suggest that inhibition of YAP/TAZ-TEAD signaling may improve the efficacy of KRAS-targeted therapy. Taken together, the covalent TEAD inhibitor BGI-9004 has demonstrated promising activity both as a single agent and in combination with other targeted agents, a favorable pharmacokinetic profile and high target selectivity in preclinical models, supporting its evaluation as a novel anti-cancer agent in clinical trials. Citation Format: Shirley Guo, Shashank Shrishrimal, Jason Cui, Guoqing Wang, Vivian Zhang, Ning Deng, Iris Dong, Anna Chen, Steve Luo, David Sperandio, Ping Cao, Wolf R. Wiedemeyer. Preclinical characterization of BGI-9004, a covalent TEAD inhibitor with exceptional anti-cancer activity and combination potential. [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 4976.