Development of SUV39H1/H2 inhibitors for immune modulation and cancer therapy – EpiCure

Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. Unlike genetic alterations, epigenetic tags are potentially erasable, allowing a reversible manipulation of cell phenotypes, and disease-associated epigenetic states can be altered through pharmacological manipulations of the molecular factors involved in the dynamics of epigenetics.
As an example, inhibitors of DNA methylation or histone deacetylase inhibitors are approved for clinical use in the treatment of haematological malignancies. Histone lysine methylation also plays a central epigenetic role in the organization of chromatin domains and the regulation of gene expression, and inhibitors of the histone methyltransferase, EZH2, are currently in phase I/II for the treatment of patients with relapsed or refractory B-cell lymphoma.
Noteworthy, the Institut Curie partners discovered that the histone-binding protein HP1 and the histone lysine methyl transferaseses (HKMT) SUV39H1/2 can be considered as a multifunctional pathway with multiple roles in chromatin dynamics, impacting on a wide range of cell functions, such as proliferation, differentiation, and maintenance of a given cellular status. For example, the loss of the SUV39H1 pathway in vivo results in skewing towards TH1 responses, decreasing lung inflammation in a murine model of allergic asthma characterized by pathological TH2 response. Furthermore, they showed that HP1a representsa hallmark of cell proliferation relevant to clinical oncology, suggesting a link between HP1, SUV39H1/H2 and cancer. Finally, SUV39H1 and SUV39H2 are also potential therapeutic targets on tumor cells themselves, an enrichment of H3K9me3 having been observed in several tumor types.
The present project aims at translating this patented academic research discoveries to the clinic, taking advantage of the drug design and development expertise of the private partner, Inventiva. We now propose to discover new, potent and selective SUV39H1 and SUV39H2 inhibitors as clinical candidates. A high throughput screening of the Inventiva proprietary compound collection comprising a diversity set and a focused HKMT library will be performed. Confirmed hits will undergo chemical optimization for improvement of physicochemical parameters, pharmacokinetics and pharmacodynamics, in particular regarding H3K9me3 marks and proliferation in cancer cells as well as T cell proliferation and differentiation.
In parallel, the expression of SUV39H1/H2 and the levels of H3K9me3/ac will be evaluated in a large panel of cancer biopsies from the Curie Institute collection, as a translational approach to identify the patient population that would benefit the most from these inhibitors. Finally, the mechanism of action of the SUV39H1 and SUV39H2 inhibitors on heterochromatin that affect tumor cell growth and/or T cell functions in vitro and in vivo will be analyzed.
This private-public collaboration will build a unique drug discovery know-how in the field of histone epigenetic modifiers leading to the identification of new compounds for clinical development in the near future.