Benzimidazolyl-pyrazolo[3,4-b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest

Benzimidazolyl-pyrazolo[3,4-b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest Научная публикация

Журнал

ACS Combinatorial Science
ISSN: 2156-8952 , E-ISSN: 2156-8944

Вых. Данные

Год: 2019, Том: 21, Номер: 12, Страницы: 805-816 Страниц : 12 DOI: 10.1021/acscombsci.9b00135

Авторы

Lichitsky Boris V. ¹ , Komogortsev Andrey N. ¹ , Dudinov Arkady A. ¹ , Krayushkin Mikhail M. ¹ , Khodot Evgenii N. ¹ , Samet Alexander V. ¹ , Silyanova Eugenia A. ¹ , Konyushkin Leonid D. ¹ , Karpov Alexei S. ² , Gorses Delphine ² , Radimerski Thomas ² , Semenova Marina N. ³ , Kiselyov Alex S. ⁴ , Semenov Victor V. ¹

Организации

1	N. D. Zelinsky Institute of Organic Chemistry, RAS, Leninsky Prospect, 47, 119991 Moscow, Russian Federation
2	Novartis Institutes for BioMedical Research, CH-4056 Basel, Switzerland
3	N. K. Kol’tsov Institute of Developmental Biology, RAS, Vavilov Street, 26, 119334 Moscow, Russian Federation
4	Myocea, Inc., 9833 Pacific Heights Blvd., San Diego, California 92121, United States

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.

Lichitsky B.V. , Komogortsev A.N. , Dudinov A.A. , Krayushkin M.M. , Khodot E.N. , Samet A.V. , Silyanova E.A. , Konyushkin L.D. , Karpov A.S. , Gorses D. , Radimerski T. , Semenova M.N. , Kiselyov A.S. , Semenov V.V.
Benzimidazolyl-pyrazolo[3,4-b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest
ACS Combinatorial Science. 2019. V.21. N12. P.805-816. DOI: 10.1021/acscombsci.9b00135 WOS Scopus OpenAlex

Web of science:	WOS:000502193700004
Scopus:	2-s2.0-85075626054
OpenAlex:	W2985845599

БД	Цитирований
OpenAlex	12
Web of science	12
Scopus	12