Design of potential new phosphoinositide 3-kinases and histone deacetylase 6 hybrid inhibitors for cancer treatment

• Grant number: 22/07275-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: October 01, 2022
• End date: March 31, 2025
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Roberto Parise Filho
• Grantee: Karoline de Barros Waitman
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 23/07455-5 - Computer-aided optimization of potential new JAK3 and histone deacetylase 6 hybrid inhibitors for hematological cancer treatment, BE.EP.DD

Abstract

Cancer is the name given to a group of diseases characterized by abnormal cell growth that can cause patient death. It is one of the leading death causes worldwide despite the numerous efforts in developing a treatment. The therapy consists of surgery, radiotherapy, and chemotherapy, aiming to remove, contain, and kill the cancer cells. Phosphoinositide 3-kinases (PI3Ks), enzymes that catalyze the phosphorylation of its substrates are among the biochemical targets used in pharmacological interventions, due to their influence on signaling and proliferation pathways commonly mutated in cancers. Other important targets are the histone deacetylase 6 (HDAC6) enzymes, responsible for the remotion of acetyl groups from histones and cytosolic proteins, regulating gene expression and functions like cell division, motility, misfolded protein degradation, apoptosis, and resistance to chemotherapeutics. However, due to tumor plasticity, single therapies can be easily evaded. The literature indicates that the development of hybrid inhibitors is a more effective approach for cancer treatment, less prone to resistance mechanisms, and able to reduce the problems associated with combined therapy. Thus, the present project aims the planning, synthesis, characterization, and cellular evaluation of hybrid PI3K-HDAC6 inhibitors as new potential anticancer agents. (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)

TAVARES, MAURICIO T.; KRUEGER, ARNE; YAN, SUN L. REI; WAITMAN, KAROLINE B.; GOMES, VINICIUS M.; DE OLIVEIRA, DAFFINY SUMAM; PAZ, FRANCIARLI; HILSCHER, SEBASTIAN; SCHUTKOWSKI, MIKE; SIPPL, WOLFGANG; et al. 1,3-Diphenylureido hydroxamate as a promising scaffold for generation of potent antimalarial histone deacetylase inhibitors. SCIENTIFIC REPORTS, v. 13, n. 1, p. 20-pg., 2023-11-30. (18/08820-0, 18/10150-3, 20/04923-0, 21/00124-8, 18/18257-1, 21/08260-8, 15/26722-8, 18/15549-1, 22/12468-6, 17/26358-0, 21/11606-3, 17/03966-4, 22/07275-4)

WAITMAN, KAROLINE B.; DE ALMEIDA, LARISSA C.; PRIMI, MARINA C.; CARLOS, JORGE A. E. G.; RUIZ, CLAUDIA; KRONENBERGER, THALES; LAUFER, STEFAN; GOETTERT, MARCIA INES; POSO, ANTTI; VASSILIADES, SANDRA V.; et al. HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 263, p. 18-pg., 2023-11-20. (23/07455-5, 21/08260-8, 22/12468-6, 21/11606-3, 22/07275-4)