Development of inhibitors of YAP-TEAD interaction for the treatment of non-small cell lung cancer (NSCLC) and pleural malignant mesothelioma – HIPPOCURE

Lung cancer accounts for 40,000 new cases yearly and 85% of patients will ultimately die from disease progression and metastasis. Thus lung cancer remains a major Health problem as the main cause of cancer death worldwide and a societal challenge since linked to tobacco smoking. Although rare, malignant pleural mesothelioma (1000 new cases yearly in France) is also an aggressive disease with median overall survival not exceeding 13 months until a recent French phase 3 trial using anti-angiogenic agent bevacizumab, which led to 19 months of medial survival. Malignant pleural mesothelioma is linked to occupational asbestosis exposure and thus also represents a societal challenge since having contaminated thousands of workers have been contaminated and will develop a mesothelioma within 40 years after occupational exposure. Mesothelioma will kill 250,000 of people worldwide in the future 30 years.
In the last few years the Hippo pathway has been recognized as a critical player in several processes involved in cancer progression, including cell proliferation, apoptosis and epithelial-to-mesenchymal transition (EMT). YAP and TAZ mediate the downstream effects of Hippo signaling, and high nuclear expression of YAP has been documented in many tumors including lung, malignant mesothelioma, colorectal, ovarian and skin cancers. When YAP translocates to the nucleus it binds to TEAD transcription factor and drives the expression of several growth factors, including CTGF, AREG, Cyr61 and cell survival factors such as survivin. This suggests that therapies targeting YAP-TEAD interaction are likely to have clinical impact for the treatment of cancer patients. However, due to the challenging nature of protein-protein interactions (PPIs), a potent inhibitor that surpasses the affinity of the YAP-TEAD interactions has not reached clinical development yet. Inventiva’s drug discovery approach relies on significant internal chemistry know-how. Indeed, a drug discovery project has started based on a combined FBLD/HTS strategies. Druggability of the TEAD protein was assessed by a fragment screen using NMR and SPR technologies, available in house. This approach, supported by assigned HSQC protein NMR information, provided hits which were used as starting points for the identification of more potent binders, and chemistry optimization is currently in progress.
The general goal of this consortium is to develop an innovative therapeutic approach based on a specific engineering- and scientific-based expertise for the treatment of lung cancer and malignant mesothelioma. Hence, scientific and technological objectives have been defined as follow:
- Identify compounds with adequate pharmacological profile targeting the YAP-TEAD interaction,
- Decode the full complexity of disease-associated genetic alterations and the intricate interaction between different players, such as the RASSF1A signaling pathway, RAS, NF2 mutations and the core Hippo pathway. This will be key to determine the optimal indications for Inventiva compounds and strong mechanism of action evidence to support the claims,
- Find promising synergistic effects with standard of care and optimize the combination therapy,
- Advance Inventiva’s compounds as rapidly as possible through regulatory preclinical steps and clinical phases.
In order for us to successfully achieve the goals of the present project, we are bringing together a "Public-Private” collaborative research effort between two academic laboratories of Institut Curie and a French PME to develop an innovative drug for the treatment of cancer. We believe that by combining Inventiva’s expertise in drug discovery with the Institut Curie’s skills in basic and translational oncology research, we can achieve rapid and significant outcomes for patients