The Hippo signaling pathway is an important regulator of cell growth and proliferation, with YAP and its paralogue TAZ as the terminal effectors of this pathway regulating the transcriptional activity of TEAD1-4. In normal cells, a well-established kinase cascade effects YAP/TAZ phosphorylation, thereby regulating its entry into the nucleus and complexation with the terminal transcription factor TEAD1-4. In cancer cells, the Hippo pathway is inactivated, leading to unphosphorylated YAP/TAZ translocation into the nucleus and promoting cell proliferation, migration, and metastasis. In fact, many cancer patient samples exhibit an overexpression of the YAP gene, suggesting that the Hippo pathway, particularly the inhibition of the terminal YAP/TAZ-TEAD complex, may be an effective approach for cancer therapy.
We herein describe the discovery and characterization of a novel YAP-TEAD inhibitor, biaryl sulfonamide 1. The structure guided lead optimization effort was accelerated by our internal capabilities of high-throughput experimentation (HTE), including parallel reaction optimization and parallel synthesis, and modern design tools, such as Free-Wilson analysis and predictive QSAR models. During the course of our studies, we prioritized desirable drug-like properties in order to deliver high quality molecules with tractable oral pharmacokinetics (PK), good physicochemical properties and off-target profiles to support in vivo characterization. Compound 1, our lead biaryl sulfonamide, was shown to disrupt the interaction of YAP and TEAD in H226 cells by co-IP, thereby suppressing TEAD-driven transcription and selectively blocking the clonogenic growth of Hippo-driven cells in a dose-dependent manner. Moreover, 1 causes a significant melting temperature shift against all four isoforms of TEAD (TEAD1-4), supporting its activity as a pan-TEAD inhibitor. Based on the excellent in vitro potency and cross-species PK profile, we advanced 1 into an efficacy study in H226 xenograft mouse model and observed good tolerability and strong in vivo response (i.e., tumor regression). Compound 1, therefore, holds promise for treating malignancies driven by altered Hippo signaling by specifically inhibiting YAP/TAZ-TEAD and the downstream transcriptional responses.

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