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.

IF 6 2区 医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-12-22 DOI:10.1016/j.ejmech.2024.117190
Christopher C. Goodis, Christian Eberly, Alexandria M. Chan, MinJung Kim, Brandon D. Lowe, Curt I. Civin, Steven Fletcher
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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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与新型多药BCL-2/FLT3 VEN-GIL混合单分子抑制剂相比,BCL-2抑制剂venetoclax(VEN)和FLT3抑制剂吉特替尼(GIL)的多药组合对急性髓性白血病细胞更有活性。
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来源期刊
CiteScore
11.70
自引率
9.00%
发文量
863
审稿时长
29 days
期刊介绍: The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.
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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. Photosensitizer associated with efflux pump inhibitors as a strategy for Photodynamic Therapy against bacterial resistance New Series of 3-Pyridyl-1,3-Thiazoles: In Vitro and In Vivo Anti-Trypanosomatidae Profile, in vitro and in silico Mechanism of Action approach Developing Dual-Responsive Quinolinium Prodrugs of 8-Hydroxyquinoline By Harnessing the Dual Chelating Sites Dodecyl creatine ester, a promising treatment to deliver creatine to neurons, achieves pharmacology efficacy in creatine transporter deficiency
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