Design of potential new kinase and histone deacetylase 6 hybrid inhibitors for hematological cancer treatment

Author(s)

Karoline de Barros Waitman

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
• Defense date: 2025-03-11

Examining board members

Roberto Parise Filho; Vinicius Gonçalves Maltarollo; Jean Leandro dos Santos; Ricardo Augusto Massarico Serafim

• Advisor: Roberto Parise Filho; Thales Kronenberger

Abstract

Hematological tumors are characterized by their high aggressiveness and malignancy, being able to acquire resistance to monotherapies. Treatment with hybrid inhibitors, particularly kinase/HDAC6 inhibitors, has the potential to block multiple signaling pathways at a time and overcome cancer resistance. The collection of articles in this thesis aims to contribute to developing such compounds. The first article is a review of kinase/HDAC inhibitors, discussing the current advances and perspectives of the field. Using that knowledge, the second article describes the design, synthesis, and biological evaluation of a new series of purinebenzohydroxamates, from which 4d-f presented IC50 50 nM in hematological cancer cell lines, linked to nanomolar inhibition of HDAC1/6, inhibition of JAKs, BTK, and TRK, besides having favorable pharmacokinetic properties. The third article describes the construction and validation of QSAR models to evaluate the inhibitory capacity of purine-benzohydroxamates, and purine-benzo-orto-anilinobenzamides in 61 hematological cancer cell lines and its associated kinase and HDAC targets. A representative set com compounds was synthesized and sent to biological evaluation, allowing the identification of 6b and 6k as anticancer agents with IC50 0.2-0.8 µM in three hematological cancer cell models, linked to HDAC6 inhibition below 2.0 nM and blockade of AKT phosphorylation at 2.0 M. Finally, to understand the reasons behind the off-target activity observed in kinases, and optimize their inhibitory potency in JAK3, while retaining the HDAC6 inhibition, SBDD was employed to design a new set of optimized hybrids. This study is described in Chapter 4 and points to a novel pathway to developing hybrid kinase/HDAC inhibitors with the potential to aid in the treatment of hematological cancers. (AU)

• 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)