Investigating resistance to 5-Azacytidine and Venetoclax in PDX models of MDS/AML

Frontiers in Oncology, Год журнала: 2025, Номер 14

Опубликована: Янв. 7, 2025

Progressing myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) is an indication for hypomethylating therapy (HMA, 5-Azacytidine (AZA)) and a BCL2 inhibitor (Venetoclax, VEN) intensive chemotherapy ineligible patients. Mouse models that engraft primary AML samples may further advance VEN + AZA resistance research. We generated set of transplantable murine PDX from MDS/AML patients who developed to compared the differences in hematopoiesis with bone marrow at genetic level. were created NSGS mice via intraosseal injection luciferase-encoding Lentivirus-infected cells patient marrow. validated PDX-leukemia tested candidate agents inhibit growth VEN/AZA-resistant AML. Transplantable arise 31 % frequency. The lower frequency not related peritransplant lethality graft, but rather loss ability short-term proliferation leukemic progenitors after 10 weeks engraftment. There exist subtle cytological changes between PDX-AML however, retain observed Based on vitro testing vivo validation models, Panobinostat Dinaciclib are very promising overcome dual resistance.

Язык: Английский

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The Peptide PROTAC Modality: A New Strategy for Drug Discovery

MedComm, Год журнала: 2025, Номер 6(4)

Опубликована: Март 24, 2025

ABSTRACT In recent years, proteolysis targeting chimera (PROTAC) technology has made significant progress in the field of drug development. Traditional drugs mainly focus on inhibiting or activating specific proteins, while PROTAC provides new ideas for treating various diseases by inducing degradation target proteins. Especially peptide PROTACs, due to their unique structural and functional characteristics, they have become a hot research topic. This review detailed description key components, mechanisms, design principles elaborates applications skin‐related diseases, oncology, other potential therapeutic fields, analyzes advantages challenges, looks forward future development prospects. The not only opens up paths development, but also solving resistance safety issues faced traditional small‐molecule drugs. Compared with PROTACs such as multitargeting, biodegradability, low toxicity, flexibility design. With deepening continuous maturity technology, are expected one important strategies discovery, providing hope treatment more intractable diseases. Peptide ushering era precision medicine.

Язык: Английский

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Decursin induces FLT3-ITD acute myeloid leukemia cell apoptosis by increasing the expression of the ubiquitin-conjugase UBE2L6

Cell Communication and Signaling, Год журнала: 2025, Номер 23(1)

Опубликована: Апрель 2, 2025

Язык: Английский

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Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 275, С. 116539 - 116539

Опубликована: Май 31, 2024

Язык: Английский

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Identification of inhibitors targeting the FLT3-ITD mutation through 4D-QSAR, in vitro, and in silico

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 282, С. 117089 - 117089

Опубликована: Ноя. 26, 2024

Язык: Английский

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Overcoming Resistance to FLT3-ITD Therapeutics

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Дек. 12, 2024

FLT3-ITD (internal tandem duplication) is a key driver of acute myeloid leukemia (AML), and several FDA-approved drugs target this mutant kinase. This Viewpoint describes the discovery inhibitors targeting point mutants development SILA123, highly potent selective type II FLT3 inhibitor. In

Язык: Английский

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Targeting FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia: Novel molecular approaches and therapeutic challenges

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 182, С. 117788 - 117788

Опубликована: Дек. 28, 2024

Язык: Английский

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