2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2024 Dec 22:285:117190. doi: 10.1016/j.ejmech.2024.117190.
Christopher C Goodis 1,  Christian Eberly 2,  Alexandria M Chan 1,  MinJung Kim 2,  Brandon D Lowe 1,  Curt I Civin 3,  Steven Fletcher 4
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD, 21201, USA.
  • 2 Center for Stem Cell Biology & Regenerative Medicine, Department of Pediatrics, University of Maryland School of Medicine, 20 Penn St., Room S103, Baltimore, MD, 21201, USA.
  • 3 Center for Stem Cell Biology & Regenerative Medicine, Departments of Pediatrics and Pharmacology, Physiology & Drug Development, University of Maryland School of Medicine, 20 Penn St., Room S103, Baltimore, MD, 21201, USA; University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St., Baltimore, MD, 21201, USA.
  • 4 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD, 21201, USA; University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center, 22 S. Greene St., Baltimore, MD, 21201, USA. Electronic address: steven.fletcher@rx.umaryland.edu.
PMID: 39813774 DOI: 10.1016/j.ejmech.2024.117190
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.

Keywords

Acute myeloid leukemia; BCL-2; Cancer; FLT3; Gilteritinib; Venetoclax; leukemia; polypharmacology.

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