Lichitsky, Boris, Komogortsev, Andrey, Dudinov, Arkady, Krayushkin, Mikhail, Khodot, Evgenii, Samet, Alexander, Karpov, Alexei, Gorses, Delphine, Radimerski, Thomas, Semenova, Marina, Kiselyov, Alex and Semenov, Victor (2019) Benzimidazolyl-pyrazolo[3,4-b]pyridinones - selective inhibitors of MOLT-4 leukemia cell growth and sea urchin embryo spiculogenesis: Target quest. ACS combinatorial science. ISSN 2156-8944; 2156-8952

Abstract

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 submicromolar 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 the 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 vs 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/-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.

Item Type:	Article
Date Deposited:	26 Nov 2019 00:45
Last Modified:	26 Nov 2019 00:45
URI:	https://oak.novartis.com/id/eprint/40260