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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.
This article was published in the following journal.
Name: European journal of medicinal chemistry
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An enzyme which catalyzes the hydrolysis of an aryl-dialkyl phosphate to form dialkyl phosphate and an aryl alcohol. It can hydrolyze a broad spectrum of organophosphate substrates and a number of aromatic carboxylic acid esters. It may also mediate an enzymatic protection of LOW DENSITY LIPOPROTEINS against oxidative modification and the consequent series of events leading to ATHEROMA formation. The enzyme was previously regarded to be identical with Arylesterase (EC 184.108.40.206).
An enzyme derived from cow's milk. It catalyzes the radioiodination of tyrosine and its derivatives and of peptides containing tyrosine.
Saturated derivatives of the steroid pregnane. The 5-beta series includes PROGESTERONE and related hormones; the 5-alpha series includes forms generally excreted in the urine.
Benzoate derivatives that contain one or more alkyl or aryl groups linked to the benzene ring structure by OXYGEN.
Organic chemicals where aryl or alkyl groups are joined by two nitrogen atoms through a double bond (R-N=N-R'; R and R' may be either aryl or alkyl). They may be used as DYES.
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