Towards the discovery and synthesis of new Arginase 1 inhibitors

Arginase 1 (Arg1) is a key hydrolase involved in the urea cycle and in the immune system. Arg1 is upregulated in various types of cancers and plays crucial roles in the regulation of tumor growth and metastasis. Thus, Arg1 is an increasingly attractive target for cancer therapy. In this thesis, we aimed to find new scaffolds. A reliable enzymatic evaluation method of chemical libraries such as that of 5-bromo-2-amino-thiazole was set up. A molecular modeling approach (SBDD) led to a better understanding of the possibilities and limitations in the Arg1 inhibitors design for the study of larger scaffolds. A Fragment-Based approach (FBDD) was then developed. A screening of coordinating motif libraries found two hits: 2-furanylboronic acid and cyclohexylboronic acid. Finally, we attempt to optimize these two hits and discussed about the challenges of obtaining such derivatives.
(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2022