HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents

Author(s):Show less -

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. ; de Souza, Vinicius A. M. ; Toledo, Monica F. Z. J. ; Hassimotto, Neuza M. A. ; Cameron, Michael D. ; Bannister, Thomas D. ; Costa-Lotufo, Leticia, V ; Machado-Neto, Joa o A. ; Tavares, Mauricio T. ; Parise-Filho, Roberto

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 263, p. 18-pg., 2023-11-20.

Abstract

A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 <= 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 mu M). Compound 4d potently inhibited multiple kinase targets of interest for anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms. (AU)

• FAPESP's process: 23/07455-5 - Computer-aided optimization of potential new JAK3 and histone deacetylase 6 hybrid inhibitors for hematological cancer treatment
• Grantee: Karoline de Barros Waitman
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 21/08260-8 - Design, synthesis and biological evaluation of hybrid inhibitors of phosphoinositide 3-kinases and histone deacetylase 6 for the treatment of hematologic malignancies
• Grantee: Roberto Parise Filho
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/12468-6 - Synthesis and biological evaluation of hybrid inhibitors for the treatment of hematologic malignancies
• Grantee: Vinícius Albuquerque Moreira de Souza
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 21/11606-3 - Investigation of the antineoplastic effects of novel PIP4K2 and HDAC inhibitors in hematologic malignancies
• Grantee: João Agostinho Machado Neto
• Support Opportunities: Regular Research Grants
• FAPESP's process: 22/07275-4 - Design of potential new phosphoinositide 3-kinases and histone deacetylase 6 hybrid inhibitors for cancer treatment
• Grantee: Karoline de Barros Waitman
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)