Abstract C133: BBT-4437, a novel, brain-penetrable, reversible pan-TEAD inhibitor targeting the Hippo signaling pathway in solid tumors

Abstract

Abstract The Hippo pathway regulates several cellular functions including cell lineage fate, proliferation, migration, apoptosis, maintenance of cell stemness and dedifferentiation, and organ size. TEA domain family members 1-4 (TEAD1-4) are evolutionarily conserved transcription factors and core components of the Hippo pathway. TEADs are functional partners of the oncoproteins YAP (Yes-associated protein) and its paralog TAZ (transcriptional co-activator with PDZ-binding motif). Mutations in components of the Hippo pathway have been implicated in several diseases, including cancer. YAP/TEAD activation has also been associated with resistance to targeted therapies by EGFR TKIs in EGFR-mutant NSCLC. Targeting TEAD transcription activity has emerged as a promising approach to addressing cancers with abnormalities in the Hippo pathway. BBT-4437 is a novel, brain-penetrable, reversible pan-TEAD inhibitor that exhibits excellent selectivity in blocking TEAD transcriptional activity in the TEAD reporter gene assay. It demonstrates nanomolar potency in inhibiting cell proliferation in NF2-deficient mesothelioma cells in vitro. BBT-4437 also inhibits the expression of downstream YAP-TEAD target genes (CCN1/CYR61, CCN2/CTGF and IGFBP3) in a concentration-dependent manner in vitro. Moreover, BBT-4437 shows synergistic effect in combination with osimertinib in the H1975 NSCLC cell line. Furthermore, daily oral administration of BBT-4437 leads to significant tumor regression in NF2-deficient H226 and H2373 mesothelioma xenograft models. BBT-4437 demonstrates favorable pharmacokinetic and ADME profiles, including excellent brain penetration. Therefore, BBT-4437 has the potential to be a best-in-class TEAD inhibitor for targeting tumors with aberrant Hippo signaling and overcoming drug resistance caused by upregulation of the Hippo pathway in the clinic. Citation Format: Leila Revollo, Jehrod Brenneman, Sharad Paudyal, Toan Nguyen, Yong-Hee Lee, Taiguang Jimmy Jin. BBT-4437, a novel, brain-penetrable, reversible pan-TEAD inhibitor targeting the Hippo signaling pathway in solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C133.