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Benzimidazolyl-pyrazolo[3,4‑b]pyridinones, Selective Inhibitors of MOLT‑4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest
journal contribution
posted on 2019-11-14, 17:33 authored by Boris
V. Lichitsky, Andrey N. Komogortsev, Arkady A. Dudinov, Mikhail M. Krayushkin, Evgenii N. Khodot, Alexander V. Samet, Eugenia A. Silyanova, Leonid D. Konyushkin, Alexei S. Karpov, Delphine Gorses, Thomas Radimerski, Marina N. Semenova, Alex S. Kiselyov, Victor V. Semenov1,3-Substituted pyrazolo[3,4-b]pyridinones 11–18 were synthesized by a three-component
condensation of Meldrum’s acid with aryl aldehydes and 1,3-substituted
5-aminopyrazoles. Their biological activity was evaluated using the in vivo phenotypic sea urchin embryo assay and the in vitro cytotoxicity screen against human cancer cell lines.
In the sea urchin embryo model, 1-benzimidazolyl-pyrazolo[3,4-b]pyridinones 11 caused inhibition of hatching
and spiculogenesis at sub-micromolar concentrations. These compounds
also selectively and potently inhibited growth of the MOLT-4 leukemia
cell line. Subsequent structure–activity relationship studies
determined the benzimidazolyl fragment as an essential pharmacophore
for both effects. We applied numerous techniques for target identification.
A preliminary QSAR target identification search did not result in
tangible leads. Attempts to prepare a relevant photoaffinity probe
that retained potency in both assays were not successful. Compounds 11 were further characterized for their activity in a wild-type versus Notch-mutant leukemia cell lines, and
in in vitro panels of kinases and matrix metalloproteinases.
Using a series of diverse modulators of spiculogenesis as standards,
we excluded multiple signaling networks including Notch, Wnt/β-catenin,
receptor tyrosine kinases (VEGF/VEGFR, FGF/FGFR), PI3K, and Raf-MEK-ERK
as possible targets of 11. On the other hand, matrix
metalloproteinase-9/hatching enzyme was identified as one potential
target.
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kinaseMOLT -4 leukemia cell lineVEGFFGFthree-component condensationphotoaffinity probevivo phenotypic sea urchin embryo assaysub-micromolar concentrationsSelective Inhibitors3Ksea urchin embryo modeltarget identificationPISea Urchin Embryo Spiculogenesiscytotoxicity screenbenzimidazolyl fragmentQSAR target identification searchNotch-mutant leukemia cell linesspiculogenesiaryl aldehydespyridinone5- aminopyrazolescancer cell linesmatrix metalloproteinasesCompounds 11
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