Computer-aided optimization of potential new JAK3 and histone deacetylase 6 hybrid inhibitors for hematological cancer treatment

• Grant number: 23/07455-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date until: November 01, 2023
• End date until: April 30, 2024
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Roberto Parise Filho
• Grantee: Karoline de Barros Waitman
• Supervisor: Wolfgang Sippl
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Martin-Luther-University of Halle-Wittenberg, Germany
• Associated to the scholarship: 22/07275-4 - Design of potential new phosphoinositide 3-kinases and histone deacetylase 6 hybrid inhibitors for cancer treatment, BP.DD

Abstract

Leukemias have low survival rates in Brazil, and the development of new treatments focused on overexpressed proteins in anticancer targets, such as kinases and HDACs, is crucial. Hybrid inhibitors that synergistically inhibit two different targets at once haves hown promising results in cancer treatment. However, maintaining selectivity is a challenge in multitargeting. This project aims to optimize selective analogues ofJAK3/HDAC6 hybrid inhibitors using computational methods as molecular dynamics simulations and enzymatic assessment in HDAC isoforms. For this, the project proposes combining the expertise of Dr. Wolfgang Sippl in optimizing epigenetic targets to propose structural models of JAK3 and HDAC6 bound to the hit compound 6d, perform virtual screening to identify novel hits, ultimately aiming to synthesize and characterize novel analogues upon returning to Brazil. The project's core method is molecular dynamics simulations, and supercomputer infrastructure in Dr. Sippl's laboratory will be utilized for running, analyzing simulations, as well as performing biochemical on-target validation of our analogues' activity. The expected out comesinclude the expansion and optimization of hybrid inhibitors, publication of manuscripts, and knowledge transfer to the LAPESSB group and pharmacy students. (AU)