Optimization of hybrid inhibitors for JAK3/HDAC6: design, synthesis, and biological evaluation

• Grant number: 24/07723-2
• Support Opportunities: Regular Research Grants
• Duration: December 01, 2024 - November 30, 2026
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Roberto Parise Filho
• Grantee: Roberto Parise Filho
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: João Agostinho Machado Neto ; Leticia Veras Costa Lotufo ; Maurício Temotheo Tavares ; Mônica Franco Zannini Junqueira Toledo ; Thales Kronenberger ; Wolfgang Sippl

Abstract

Polypharmacology is emerging as an effective strategy for treating multifactorial diseases such as cancer. Hybrid inhibitors, capable of targeting two distinct pathways, have shown synergistic gains in treatment efficacy, mitigating the development of resistance. In our Lapessb laboratory, nanomolar-potent HDAC and micromolar-potent JAK3 hybrid inhibitors were developed, demonstrating anti-tumor activity at 40 nM in hematological tumors with a safe pharmacokinetic profile. Despite their promise, challenges persist in developing such inhibitors, including balancing potency on desired targets, reducing activity on undesired targets, and maintaining desired pharmacokinetic characteristics. Thus, the goal is to optimize inhibitors favoring a selective profile for JAK3 and HDAC6 through molecular modifications such as the insertion of electrophilic groups, variation of the ZBG position, and introduction of bulkier groups to the cap portion. In silico evaluations will simulate the most favorable modifications for the desired activity, and the top-ranked compounds will be synthesized, chemically characterized, and biologically evaluated for their activity in hematological tumor cells. This research aims to elucidate the mechanism of action and enzymatic activity on the targets, ultimately seeking to obtain promising compounds for the treatment of hematological malignancies. (AU)