Within our ERC CoG grant, RSHEALTH, our group has contributed to the to the preclinical development of chemical inhibitors of the ATR kinase as anticancer agents, that are now in clinical trials by several companies. During the course of our investigations, we also made important advances in developing inhibitors of SETD8, another interesting cancer-related target. SETD8 is a histone methyltransferase known to play important roles in DNA replication and repair. Evidence indicating that targeting SETD8 could be interesting for cancer therapy has been building up in recent years. For instance, SETD8 is overexpressed in a wide range of cancers, and recent works identified SETD8 as a specific vulnerability in High-Risk Neuroblastoma or MYC-driven Medulloblastomas. Unfortunately, all available SETD8 inhibitors have low potency and poor pharmacological properties, and none has progressed to the clinic. We here propose to capitalize in our strengths in academic drug development, and our experience in transferring our inhibitors to the industry, in order to facilitate the clinical development SETD8 inhibitors. Our proposal includes objectives that will help us improve the quality of our inhibitors, valorise them in preclinical cancer models and develop companion biomarkers that would be used for patient stratification. All of this would be integrated within a business plan that should facilitate a coherent development of this line of work oriented towards the clinical development of SETD8 inhibitors for the benefit of cancer patients.
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