2. Academic Validation
  3. Novel water-soluble and highly efficient dual type I/II next generation inhibitors of FMS-like tyrosine kinase 3 (FLT3)

Novel water-soluble and highly efficient dual type I/II next generation inhibitors of FMS-like tyrosine kinase 3 (FLT3)

  • Eur J Med Chem. 2025 Oct 15:296:117849. doi: 10.1016/j.ejmech.2025.117849.
Andreas Sellmer 1,  Marina Able 2,  Karsten Spiekermann 3,  Maria Reinecke 4,  Bernhard Kuster 5,  Kirsten Utpatel 6,  Lukas Wirth 7,  Herwig Pongratz 8,  Nicole Plank 9,  Pierre Koch 10,  Sigurd Elz 11,  Amrei Fischer 12,  Belay Tizazu 13,  Heinz-Herbert Fiebig 14,  Stefan Dove 15,  Siavosh Mahboobi 16
Affiliations

Affiliations

  • 1 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: Andreas.Sellmer@t-online.de.
  • 2 Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany. Electronic address: marina.able@med.uni-muenchen.de.
  • 3 Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, a Partnership Between DKFZ and LMU University Hospital, Munich, Germany; Bavarian Cancer Research Center (BZKF), Germany. Electronic address: karsten.spiekermann@med.uni-muenchen.de.
  • 4 Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, 85354, Freising, Germany. Electronic address: maria.reinecke@tum.de.
  • 5 German Cancer Consortium (DKTK), Partner Site Munich, a Partnership Between DKFZ and LMU University Hospital, Munich, Germany; Proteomics and Bioanalytics, TUM School of Life Sciences, Technical University of Munich, 85354, Freising, Germany; Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS), Technical University of Munich, 85354, Freising, Germany. Electronic address: kuster@tum.de.
  • 6 Institute of Pathology, University of Regensburg, 93040, Regensburg, Germany. Electronic address: Kirsten.Utpatel@klinik.uni-regensburg.de.
  • 7 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: Lukas.Wirth@chemie.uni-regensburg.de.
  • 8 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: Herwig.Pongratz@chemie.uni-regensburg.de.
  • 9 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: nicole.plank@chemie.uni-regensburg.de.
  • 10 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: pierre.koch@chemie.uni-regensburg.de.
  • 11 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: Sigurd.Elz@chemie.uni-regensburg.de.
  • 12 Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, a Partnership Between DKFZ and LMU University Hospital, Munich, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: amrei.fischer@med.uni-muenchen.de.
  • 13 Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany. Electronic address: belay.tizazu@med.uni-muenchen.de.
  • 14 4HF Biotec GmbH, Am Flughafen 14, 79108, Freiburg, Germany. Electronic address: fiebig@4hf.eu.
  • 15 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: Stefan.Dove@chemie.uni-regensburg.de.
  • 16 Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, 93040, Regensburg, Germany. Electronic address: Siavosh.Mahboobi@chemie.uni-regensburg.de.
PMID: 40517575 DOI: 10.1016/j.ejmech.2025.117849
Abstract

Mutations of the FMS-like tyrosine kinase (FLT3) occur in acute myeloid leukemia (AML) and are associated with very poor prognosis. Available FLT3 inhibitors are potent but either show a lack of selectivity regarding Other tyrosine kinases or only transient efficacy due to emerging resistance under therapy. Water-soluble derivatives of the tyrosine kinase inhibitor Marbotinib are highly selective dual-type I/II inhibitors of FLT3. The bisarylmethanone-based compound 29 and its carbamate derivative 42 show excellent results in various biological tests. They inhibit FLT3-ITD (internal tandem duplication) as well as therapy-associated FLT3-TKD point mutations. Additionally, good water solubility and consequently biological availability was achieved by attaching amine functions to appropriate scaffold positions, suggested by modeling of inhibitor binding at inactive and active FLT3 states. Subsequent formation of different salts led to very promising results in in vivo studies and improvements compared to midostaurin (1b), Quizartinib (7), Marbotinib 10 and its carbamate 11c.

Keywords

Acute myleoid leukemia; FLT3 mutations; In vivo mouse model; Type I/II inhibitor; Tyrosine kinase inhibitor.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z