Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping
FLT3 kinase is a potential drug target in acute myeloid leukemia (AML). Patients with FLT3 mutations typically have higher relapse rates and worse outcomes than patients without FLT3 mutations. In this study, we investigated the suitability of various heterocycles as central cores of FLT3 inhibitors, including thieno[3,2-d]pyrimidine, pyrazolo[1,5-a]pyrimidine, imidazo[4,5-b]pyridine, pyrido[4,3-d]pyrimidine, and imidazo[1,2-b]pyridazine. Our assays revealed a series of imidazo[1,2-b]pyridazines with high potency against FLT3. Compound 34f showed nanomolar inhibitory activity against recombinant FLT3-ITD and FLT3-D835Y (IC50 values 4 and 1 nM, respectively) as well as in the FLT3-ITD-positive AML cell lines MV4-11, MOLM-13, and MOLM-13 expressing the FLT3-ITD-D835Y mutant (GI50 values of 7, 9, and 4 nM, respectively). In contrast, FLT3-independent cell lines were much less sensitive. In vitro experiments confirmed suppression of FLT3 downstream signaling pathways. Finally, the treatment of MV4-11 xenograft-bearing mice with 34f at doses of 5 and 10 mg/kg markedly blocked tumor growth without any adverse effects.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 66(2023), 16 vom: 24. Aug., Seite 11133-11157 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Břehová, Petra [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
449GLA0653 |
|---|
| Anmerkungen: |
Date Completed 25.08.2023 Date Revised 30.08.2023 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.3c00575 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM360355730 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM360355730 | ||
| 003 | DE-627 | ||
| 005 | 20231226082836.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.3c00575 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1201.xml |
| 035 | |a (DE-627)NLM360355730 | ||
| 035 | |a (NLM)37535845 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Břehová, Petra |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-b]pyridazine Derivatives Identified by Scaffold Hopping |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 25.08.2023 | ||
| 500 | |a Date Revised 30.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a FLT3 kinase is a potential drug target in acute myeloid leukemia (AML). Patients with FLT3 mutations typically have higher relapse rates and worse outcomes than patients without FLT3 mutations. In this study, we investigated the suitability of various heterocycles as central cores of FLT3 inhibitors, including thieno[3,2-d]pyrimidine, pyrazolo[1,5-a]pyrimidine, imidazo[4,5-b]pyridine, pyrido[4,3-d]pyrimidine, and imidazo[1,2-b]pyridazine. Our assays revealed a series of imidazo[1,2-b]pyridazines with high potency against FLT3. Compound 34f showed nanomolar inhibitory activity against recombinant FLT3-ITD and FLT3-D835Y (IC50 values 4 and 1 nM, respectively) as well as in the FLT3-ITD-positive AML cell lines MV4-11, MOLM-13, and MOLM-13 expressing the FLT3-ITD-D835Y mutant (GI50 values of 7, 9, and 4 nM, respectively). In contrast, FLT3-independent cell lines were much less sensitive. In vitro experiments confirmed suppression of FLT3 downstream signaling pathways. Finally, the treatment of MV4-11 xenograft-bearing mice with 34f at doses of 5 and 10 mg/kg markedly blocked tumor growth without any adverse effects | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a pyridazine |2 NLM | |
| 650 | 7 | |a 449GLA0653 |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyridazines |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a fms-Like Tyrosine Kinase 3 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a FLT3 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 700 | 1 | |a Řezníčková, Eva |e verfasserin |4 aut | |
| 700 | 1 | |a Škach, Kryštof |e verfasserin |4 aut | |
| 700 | 1 | |a Jorda, Radek |e verfasserin |4 aut | |
| 700 | 1 | |a Dejmek, Milan |e verfasserin |4 aut | |
| 700 | 1 | |a Vojáčková, Veronika |e verfasserin |4 aut | |
| 700 | 1 | |a Šála, Michal |e verfasserin |4 aut | |
| 700 | 1 | |a Kovalová, Markéta |e verfasserin |4 aut | |
| 700 | 1 | |a Dračínský, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Dolníková, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Strmeň, Timotej |e verfasserin |4 aut | |
| 700 | 1 | |a Kinnertová, Monika |e verfasserin |4 aut | |
| 700 | 1 | |a Chalupský, Karel |e verfasserin |4 aut | |
| 700 | 1 | |a Dvořáková, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Gucký, Tomáš |e verfasserin |4 aut | |
| 700 | 1 | |a Mertlíková Kaiserová, Helena |e verfasserin |4 aut | |
| 700 | 1 | |a Klener, Pavel |e verfasserin |4 aut | |
| 700 | 1 | |a Nencka, Radim |e verfasserin |4 aut | |
| 700 | 1 | |a Kryštof, Vladimír |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 66(2023), 16 vom: 24. Aug., Seite 11133-11157 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:66 |g year:2023 |g number:16 |g day:24 |g month:08 |g pages:11133-11157 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.3c00575 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 66 |j 2023 |e 16 |b 24 |c 08 |h 11133-11157 | ||