A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia

Andreas Sellmer; Bernadette Pilsl; Mandy Beyer; Herwig Pongratz; Lukas Wirth; Sigurd Elz; Stefan Dove; Sven Julian Henninger; Karsten Spiekermann; Harald Polzer; Susan Klaeger; Bernhard Kuster; Frank D. Böhmer; Heinz Herbert Fiebig; Oliver H. Krämer; Siavosh Mahboobi

doi:10.1016/j.ejmech.2020.112232

A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia

Andreas Sellmer, Bernadette Pilsl, Mandy Beyer, Herwig Pongratz, Lukas Wirth, Sigurd Elz, Stefan Dove, Sven Julian Henninger, Karsten Spiekermann, Harald Polzer, Susan Klaeger, Bernhard Kuster, Frank D. Böhmer, Heinz Herbert Fiebig, Oliver H. Krämer, Siavosh Mahboobi

Chair of Bioanalytics

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.

Original language	English
Article number	112232
Journal	European Journal of Medicinal Chemistry
Volume	193
DOIs	https://doi.org/10.1016/j.ejmech.2020.112232
State	Published - 1 May 2020

Keywords

Acute myeloid leukemia
FLT3
FLT3 D835Y
FLT3-ITD
Tyrosine kinase inhibitor

Access to Document

10.1016/j.ejmech.2020.112232

Cite this

Sellmer, A., Pilsl, B., Beyer, M., Pongratz, H., Wirth, L., Elz, S., Dove, S., Henninger, S. J., Spiekermann, K., Polzer, H., Klaeger, S., Kuster, B., Böhmer, F. D., Fiebig, H. H., Krämer, O. H., & Mahboobi, S. (2020). A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia. European Journal of Medicinal Chemistry, 193, Article 112232. https://doi.org/10.1016/j.ejmech.2020.112232

@article{4e7824aa9506422f94c6434956f99b22,

title = "A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia",

abstract = "Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.",

keywords = "Acute myeloid leukemia, FLT3, FLT3 D835Y, FLT3-ITD, Tyrosine kinase inhibitor",

author = "Andreas Sellmer and Bernadette Pilsl and Mandy Beyer and Herwig Pongratz and Lukas Wirth and Sigurd Elz and Stefan Dove and Henninger, {Sven Julian} and Karsten Spiekermann and Harald Polzer and Susan Klaeger and Bernhard Kuster and B{\"o}hmer, {Frank D.} and Fiebig, {Heinz Herbert} and Kr{\"a}mer, {Oliver H.} and Siavosh Mahboobi",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Masson SAS",

year = "2020",

month = may,

day = "1",

doi = "10.1016/j.ejmech.2020.112232",

language = "English",

volume = "193",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson s.r.l.",

}

Sellmer, A, Pilsl, B, Beyer, M, Pongratz, H, Wirth, L, Elz, S, Dove, S, Henninger, SJ, Spiekermann, K, Polzer, H, Klaeger, S, Kuster, B, Böhmer, FD, Fiebig, HH, Krämer, OH & Mahboobi, S 2020, 'A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia', European Journal of Medicinal Chemistry, vol. 193, 112232. https://doi.org/10.1016/j.ejmech.2020.112232

TY - JOUR

T1 - A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia

AU - Sellmer, Andreas

AU - Pilsl, Bernadette

AU - Beyer, Mandy

AU - Pongratz, Herwig

AU - Wirth, Lukas

AU - Elz, Sigurd

AU - Dove, Stefan

AU - Henninger, Sven Julian

AU - Spiekermann, Karsten

AU - Polzer, Harald

AU - Klaeger, Susan

AU - Kuster, Bernhard

AU - Böhmer, Frank D.

AU - Fiebig, Heinz Herbert

AU - Krämer, Oliver H.

AU - Mahboobi, Siavosh

PY - 2020/5/1

Y1 - 2020/5/1

N2 - Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.

AB - Mutants of the FLT3 receptor tyrosine kinase (RTK) with duplications in the juxtamembrane domain (FLT3-ITD) act as drivers of acute myeloid leukemia (AML). Potent tyrosine kinase inhibitors (TKi) of FLT3-ITD entered clinical trials and showed a promising, but transient success due to the occurrence of secondary drug-resistant AML clones. A further caveat of drugs targeting FLT3-ITD is the co-targeting of other RTKs which are required for normal hematopoiesis. This is observed quite frequently. Therefore, novel drugs are necessary to treat AML effectively and safely. Recently bis(1H-indol-2-yl)methanones were found to inhibit FLT3 and PDGFR kinases. In order to optimize these agents we synthesized novel derivatives of these methanones with various substituents. Methanone 16 and its carbamate derivative 17b inhibit FLT3-ITD at least as potently as the TKi AC220 (quizartinib). Models indicate corresponding interactions of 16 and quizartinib with FLT3. The activity of 16 is accompanied by a high selectivity for FLT3-ITD.

KW - Acute myeloid leukemia

KW - FLT3

KW - FLT3 D835Y

KW - FLT3-ITD

KW - Tyrosine kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85081957213&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2020.112232

DO - 10.1016/j.ejmech.2020.112232

M3 - Article

C2 - 32199135

AN - SCOPUS:85081957213

SN - 0223-5234

VL - 193

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 112232

ER -

A series of novel aryl-methanone derivatives as inhibitors of FMS-like tyrosine kinase 3 (FLT3) in FLT3-ITD-positive acute myeloid leukemia

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this