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ACS Comb Sci 2019 Dec 09;2112:805-816. doi: 10.1021/acscombsci.9b00135.
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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.

Lichitsky BV , Komogortsev AN , Dudinov AA , Krayushkin MM , Khodot EN , Samet AV , Silyanova EA , Konyushkin LD , Karpov AS , Gorses D , Radimerski T , Semenova MN , Kiselyov AS , Semenov VV .

1,3-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.

PubMed ID: 31689077
Article link: ACS Comb Sci

Genes referenced: fgf fgfr3 LOC100887844 LOC100893907 LOC115919910 LOC115922368 LOC576066 LOC586734 LOC588766 LOC594353 mmp7 mos srpl