Designing of CDK2 covalent allosteric inhibitors as promising candidates for cancer treatment

• Grant number: 22/14459-4
• Support Opportunities: Scholarships abroad - Research
• Start date until: July 01, 2023
• End date until: June 30, 2024
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Jeanine Giarolla Vargas
• Grantee: Jeanine Giarolla Vargas
• Host Investigator: Ingrid Gunda Georg
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: University of Minnesota (U of M), United States

Abstract

Cancer is a global health concern. There are several problems related to chemotherapy, such as toxicity and resistance to drugs available for therapy. Thus, there is great motivation from the scientific community to engage in research, above all, to reduce the suffering of those affected. In view of the urgent needs for better anticancer drugs, the objective of this project is the design of inhibitors active against Cyclin-Dependent Kinase 2 (CDK2). CDK2 is involved in the cell division process and, in cancer, is highly activated. There are reports of compounds acting in the ATP pocket. However, they are often not selective for CDK2 and, consequently, have considerable toxicity. In our proposal, the mechanism of action will be focused on an allosteric site in CDK2 through covalent interaction, aiming to investigate how covalent allosteric inhibition of CDK2 can affect conformational protein changes and dynamic properties. We present a rational in silico design using structure-based virtual screening, molecular docking simulations and evaluation of physicochemical properties of hit molecules, as well as biological assays to validate our computational findings (eg enzyme inhibition assays, among others). We hope to contribute to this area of knowledge with an innovative proposal, especially regarding novel covalent allosteric inhibitors, which are expected to be useful, in the future, for saving lives and to reduce the suffering of cancer patients. (AU)