ArticleEuropean journal of medicinal chemistry2025
The polypharmacy combination of the BCL-2 inhibitor venetoclax (VEN) and the FLT3 inhibitor gilteritinib (GIL) is more active in acute myeloid leukemia cells than novel polypharmacologic BCL-2/FLT3 VEN-GIL hybrid single-molecule inhibitors.
Article in European journal of medicinal chemistry, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed.
- Proteolysis Targeting Chimera (PROTAC) Linkerology Enhances the CDK-Degradation Selectivity Profile of a Multi-CDK Inhibitor: Discovery of Potent, Anti-Leukemic CDK9 Degraders.ACS pharmacology & translational science · 2026Article
- Review
- Novel molecular mechanisms of FLT3 deregulation: from the acute myeloid leukemia experience to therapeutic insights in acute lymphoblastic leukemia.Molecular cancer · 2025Review
- Razing the scaffolding: the elimination of non-catalytic functions of kinases through targeted protein degradation.RSC medicinal chemistry · 2025Review
- Augmenting the Anti-Leukemic Activity of the BCL-2 Inhibitor Venetoclax Through Its Transformation Into Polypharmacologic Dual BCL-2/HDAC1 and Dual BCL-2/HDAC6 Inhibitors.Drug development research · 2025Article
- Current Knowledge of the Integrated Stress Response in the Development and Management of Acute Myeloid Leukemia: A Novel Target with Encouraging Progress.Drug design, development and therapy · 2025Review
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
Current treatments for acute myeloid leukemias (AMLs) cure fewer than 30 % of patients. This low efficacy is due, in part, to the inter-patient and intra-patient heterogeneity of AMLs; accordingly, all current AML treatment regimens involve drug combinations (polypharmacy). A recently-completed clinical trial in relapsed/refractory AML using a combination of two newer targeted antileukemics, the BCL-2 inhibitor venetoclax (VEN) plus the FLT3 inhibitor gilteritinib (GIL), yielded highly promising results for this two-drug polypharmacy combination. Polypharmacology - wherein a single drug molecule that inhibits two or more biological targets is created - has been proposed to offer superior therapeutic results, as compared to the corresponding polypharmacy approach. Herein, we designed and synthesized several polypharmacologic dual BCL-2/FLT3 hybrid single-molecule inhibitors by tethering VEN to GIL, through their solvent-exposed domains. While the in vitro antileukemic activity of the two-drug VEN + GIL polypharmacy combination proved superior to our focused library of VEN-GIL hybrids, alternative grafting points on GIL may yield improved results for future hybrid compounds.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.