TEAD Inhibitors for the Treatment of Hippo Pathway-Dependent Cancers

Project Overview

• Dysregulation of the Hippo pathway has been closely linked to tumor growth in several forms of cancer. However, disruption of the Hippo pathway has been difficult because many of the pathway’s core kinases are tumor suppressors and, thus, inappropriate targets for cancer therapies. 
• A unique emerging target of interest in the Hippo pathway are transcriptional enhanced associated domain (TEAD) transcription factors that are critical modulators of the pathway.
• Dana-Farber researchers have created a portfolio of TEAD inhibitors.
• The portfolio is available for licensing or for further collaborative development. 

Technology

A program initiated by researchers at Dana-Farber resulted in a portfolio of published and further optimized unpublished pan-TEAD and TEAD1-specific covalent inhibitors. Resulting lead compounds exhibit nanomolar in vitro potency and in vivo anti-tumor efficacy in a Hippo-activated malignant pleural mesothelioma tumor model.

Furthermore, lead compounds are well tolerated in mice showing a promising pharmacodynamic profile. Integrated pharmacology shows favorable drug-like properties and mouse pharmacokinetic profile/data predicting good oral bioavailability with drug exposure levels commensurate with efficacy. 

Benefits of the program:

• Emerging clinical data validate the Hippo pathway. 
• Improved metabolic stability compared to published compounds (Lu & Gray, J Med Chem, 2023).
• Covalent inhibition expected to lead to enhanced selectivity and potency. 
• Portfolio includes both pan-TEAD and TEAD1-specific inhibitors. 
• Advanced compounds expedite entry into IND-enabling studies.

Further Details: 

Lu and Gray, et al. Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors J. Med. Chem. 2023, 4617-4632.

Fan and Gray, et al. Covalent disruptor of YAP-TEAD association suppresses defective Hippo signaling. eLife 2022, e78810.

Team Members: Nathanael S. Gray, PhD, Yang Gao, PhD, Tinghu Zhang, PhD

Applications

• Primary indications include malignant pleural mesothelioma, meningioma, epithelioid hemangioendothelioma (EHE), and non-small cell lung cancer. 
• Secondary indications include breast, ovarian, lung, liver, head and neck, and colon cancer. 
• Combination therapy to target drug-tolerant persister cells that emerge with upregulated Hippo signaling after treatment with targeted therapy such as KRAS and EGFR inhibition.

Opportunities

Dana-Farber is seeking the right partner to develop this asset through an exclusive license or for further industry-sponsored co-development.