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.

26 Sep 2024·Journal of Medicinal Chemistry

Heat Shock Protein 90 Interactome-Mediated Proteolysis Targeting Chimera (HIM-PROTAC) Degrading Glutathione Peroxidase 4 to Trigger Ferroptosis

Article

Author: Dong, Jinyun ; Cao, Fei ; Cheng, Xiangdong ; Ding, Guangyu ; Ma, Furong ; Li, Haobin ; Li, Juan ; Liang, Hui ; Cai, Maohua ; Qin, Jiang-Jiang ; Li, Yulong

Targeted protein degradation (TPD) is an emerging therapeutic paradigm aimed at eliminating the disease-causing protein with aberrant expression. Herein, we report a new approach to inducing intracellular glutathione peroxidase 4 (GPX4) protein degradation to trigger ferroptosis by bridging the target protein to heat shock protein 90 (HSP90), termed HSP90 interactome-mediated proteolysis targeting chimera (HIM-PROTAC). Different series of HIM-PROTACs were synthesized and evaluated, and two of them, GDCNF-2/GDCNF-11 potently induced ferroptosis via HSP90-mediated ubiquitin-proteasomal degradation of GPX4 in HT-1080 cells with DC₅₀ values of 0.18 and 0.08 μM, respectively. In particular, GDCNF-11 showed 15-fold more ferroptosis selectivity over GPX4 inhibitor ML162. Moreover, these two degraders effectively suppress tumor growth in the mice model with relatively low toxicity as compared to the combination therapy of GPX4 and HSP90 inhibitors. In general, this study demonstrated the feasibility of degrading GPX4 via HSP90 interactome, and thus provided a significant complement to existing TPD strategies.

01 Aug 2024·Bioorganic Chemistry

Discovery of a potent Gilteritinib-based FLT3-PROTAC degrader for the treatment of Acute myeloid leukemia

Article

Author: Cui, Zhenzhen ; Kang, Di ; Rong, Quanjin ; Ye, Lei ; Zhou, Haikun ; Sun, Yu ; Hu, Lihong ; Zhang, Qijian ; Wang, Junwei ; Wang, Dan ; Jin, Jiaming

Fms-like tyrosine receptor kinase 3 (FLT3) proteolysis targeting chimeras (PROTACs) emerge as a promising approach to overcome the limitations of FLT3 inhibitors, while the development of orally bioavailable FLT3-PROTACs faces great challenges. Here, we report the rational design and evaluation of a series of Gilteritinib-based FLT3-PROTACs. Among them, B3-2 exhibited the strongest antiproliferative activity against FLT3-ITD mutant AML cells, and significantly induced FLT3-ITD protein degradation. Mechanistic investigations demonstrated that B3-2 induced FLT3-ITD degradation in a ubiquitin-proteasome-dependent manner. More importantly, B3-2 exhibited an oral bioavailability of 5.65%, and oral administration of B3-2 showed good antitumor activity in MV-4-11 xenograft models. Furthermore, B3-2 showed strong antiproliferative activity against FLT3 resistant mutations, highlighting its potential in overcoming drug resistance.

100 Deals associated with FLT3-targeting PROTACs(China Pharmaceutical University)

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Myeloid Leukemia	Preclinical	CN	Southern Medical University	15 Mar 2024
Acute Myeloid Leukemia	Preclinical	CN	China Pharmaceutical University	15 Mar 2024

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