FLT3-PROTACs for combating AML resistance: Analytical overview on chimeric agents developed, challenges, and future perspectives.

Autor: Hesham HM; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt., Dokla EME; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt. Electronic address: emanelawady@pharma.asu.edu.eg., Elrazaz EZ; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt., Lasheen DS; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt., Abou El Ella DA; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt. Electronic address: dalal@pharma.asu.edu.eg.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2024 Nov 05; Vol. 277, pp. 116717. Date of Electronic Publication: 2024 Aug 01.
DOI: 10.1016/j.ejmech.2024.116717
Abstrakt: The urgent and unmet medical demand of acute myeloid leukemia (AML) patients has driven the drug discovery process for expansion of the landscape of AML treatment. Despite the several agents developed for treatment of AML, more than 60 % of treated patients undergo relapse again after re-emission, thus, no complete cure for this complex disease has been reached yet. Targeted oncoprotein degradation is a new paradigm that can be employed to solve drug resistance, disease relapse, and treatment failure in complex diseases as AML, the most lethal hematological malignancy. AML is an aggressive blood cancer form and the most common type of acute leukemia, with bad outcomes and a very poor 5-year survival rate. FLT3 mutations occur in about 30 % of AML cases and FLT3-ITD is associated with poor prognosis of this disease. Prevalent FLT3 mutations include internal tandem duplication and point mutations (e.g., D835) in the tyrosine kinase domain, which induce FLT3 kinase activation and result in survival and proliferation of AML cells again. Currently approved FLT3 inhibitors suffer from limited clinical efficacy due to FLT3 reactivation by mutations, therefore, alternative new treatments are highly needed. Proteolysis-targeting chimera (PROTAC) is a bi-functional molecule that consists of a ligand of the protein of interest, FLT3 inhibitor in our case, that is covalently linked to an E3 ubiquitin ligase ligand. Upon FLT3-specific PROTAC binding to FLT3, the PROTAC can recruit E3 for FLT3 ubiquitination, which is subsequently subjected to proteasome-mediated degradation. In this review we tried to address the question if PROTAC technology has succeeded in tackling the disease relapse and treatment failure of AML. Next, we explored the latest FLT3-targeting PROTACs developed in the past few years such as quizartinib-based PROTACs, dovitinib-based PROTACs, gilteritinib-based PROTACs, and others. Then, we followed with a deep analysis of their advantages regarding potency improvement and overcoming AML drug resistance. Finally, we discussed the challenges facing these chimeric molecules with proposed future solutions to circumvent them.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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