Design of Novel Arginase 1 Inhibitors for Re-Establishing Anti-Tumor Immune Response

• Applicant: Professor Dr. Gerhard Wolber
• Subject Area: Pharmacy
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 244857959

Arginase 1 (Arg1) is a key metalloenzyme of the urea cycle converting L-arginine into L-ornithine. Recent studies show that Arg1 is upregulated in tumor cells, tumor-regulated dendritic cells and myeloid derived suppressor cells. This overexpression accelerates Arginine degradation and represents an essential mechanism for tumor-induced immunosuppression preventing rejection of cancer cells. Furthermore, Arg1 is considered a promising target for the management of diseases associated with aberrant L-arginine homeostasis such as asthma, cardiovascular diseases, and erectile dysfunction. In this project, we plan to implement an experimentally driven computational design workflow for the discovery of novel Arg1 modulators.Current lead-structures for small molecule inhibitors of Arginase all contain amino acid moieties and/or bind covalently to the protein posing challenges for further optimization and enzyme selectivity. Due to the promising therapeutic potential of Arg1 there is a need for identifying novel chemical scaffolds that bind to the enzyme. A conserved manganese ion in the catalytic site and the recent availability of several crystal structures offer the opportunity for rational design of selective inhibitors. To achieve this goal we will implement an iterative fragment-based design strategy for the identification of novel Arg1 inhibitors. The proposed approach includes the identification of potentially binding fragments by virtual screening followed by an experimental validation of their inhibition potency against Arg1. The most potent fragments will be utilized as building blocks for the design and the synthesis of biologically active molecules. Linking of initially identified fragments and compound optimization will be performed using dynamic 3D pharmacophores that include information on conformational flexibility and resulting interaction potential of the ligands with Arg1 in aqueous solution over a certain time-scale. The main advantage of these dynamic 3D pharmacophores is that the complexity of the molecular dynamics simulation can be used in a single step for highly efficient virtual screening of large compound libraries. The newly identified inhibitors will represent new lead structures for the treatment of the above-mentioned diseases, serve as pharmacological tools for understanding Arg1 and lead to new chemical classes of anti-cancer drugs.

• DFG Programme: Research Grants
• International Connection: Belgium
• Participating Persons: Professor Dr. Raphael Frederick; Professor Dr. Lionel Pochet; Professor Dr. Johan Wouters