Design, synthesis and biological evaluation of hybrid inhibitors of phosphoinositide 3-kinases and histone deacetylase 6 for the treatment of hematologic malignancies

• Grant number: 21/08260-8
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2022
• End date: February 29, 2024
• 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
• City of the host institution: São Paulo
• Associated researchers: João Agostinho Machado Neto ; Leticia Veras Costa Lotufo ; Maurício Temotheo Tavares ; Mônica Franco Zannini Junqueira Toledo ; Thales Kronenberger

Abstract

Several studies pointed out the advantages of the multi-target approach in cancer treatment. In this context, the hybridization of pharmacophoric groups with distinct action can be a valuable strategy in the discovery of molecules capable of inhibiting two - or more - cellular signaling pathways, increasing the efficacy, and improving the therapeutic regimen of chemotherapy treatment. Phosphoinositide 3-kinase (PI3K) and histone deacetylase 6 (HDAC6) inhibitors, when used in combination, have shown synergism of action and increased antineoplastic efficacy, especially in hematological tumors. Herein, this project aims the design and synthesis of hybrid dual-action PI3K´-HDAC6 inhibitors, as well as the biological evaluation against a panel of hematological and solid tumors. Moreover, the potency and selectivity will be verified against the isolated molecular targets. Computational studies will be conducted to better understand the interaction of these inhibitors with their biological targets and also drive the synthesis. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

VASSILIADES, SANDRA VALERIA; BORGES, LARA GIMENEZ; GIAROLLA, JEANINE; PARISE-FILHO, ROBERTO. Folate Pathway Inhibitors, An Underestimated and Underexplored Molecular Target for New Anti-tuberculosis Agents. MINI-REVIEWS IN MEDICINAL CHEMISTRY, v. 23, n. 17, p. 22-pg., 2023-01-01. (21/08260-8, 17/00689-0)

WAITMAN, KAROLINE; PARISE-FILHO, ROBERTO. New kinase and HDAC hybrid inhibitors: recent advances and perspectives. Future Medicinal Chemistry, v. 14, n. 10, p. 22-pg., 2022-05-11. (21/08260-8)