Dataset Information

Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity.

ABSTRACT: Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors (S1P1-5) to regulate cell growth and survival and has been implicated in a variety of diseases including cancer and sickle cell disease. As the key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmaceutical inhibition. In this article, we describe the design, synthesis, and biological evaluation of aminothiazole-based guanidine inhibitors of SphK. Surprisingly, combining features of reported SphK1 inhibitors generated SphK1/2 dual inhibitor 20l (SLC4011540) (hSphK1 Ki = 120 nM, hSphK2 Ki = 90 nM) and SphK2 inhibitor 20dd (SLC4101431) (Ki = 90 nM, 100-fold SphK2 selectivity). These compounds effectively decrease S1P levels in vitro. In vivo administration of 20dd validated that inhibition of SphK2 increases blood S1P levels.

SUBMITTER: Childress ES

PROVIDER: S-EPMC6047346 | biostudies-other | 2017 May

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity.

Childress Elizabeth S ES Kharel Yugesh Y Brown Anne M AM Bevan David R DR Lynch Kevin R KR Santos Webster L WL

Journal of medicinal chemistry 20170425 9

Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that interacts with its five G-protein coupled receptors (S1P<sub>1-5</sub>) to regulate cell growth and survival and has been implicated in a variety of diseases including cancer and sickle cell disease. As the key mediators in the synthesis of S1P, sphingosine kinase (SphK) isoforms 1 and 2 have attracted attention as viable targets for pharmaceutical inhibition. In this article, we describe the design, synthesis, and biological ...[more]

PMID: 28406646

Dataset Information

Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity.

Publications

Transforming Sphingosine Kinase 1 Inhibitors into Dual and Sphingosine Kinase 2 Selective Inhibitors: Design, Synthesis, and in Vivo Activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Similar Datasets

Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors.
| S-EPMC3748591 | biostudies-literature

Synthesis of selective inhibitors of sphingosine kinase 1.
| S-EPMC3608193 | biostudies-literature

Structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors.
| S-EPMC4557804 | biostudies-literature

Design, synthesis, and structure-activity relationship of substrate competitive, selective, and in vivo active triazole and thiadiazole inhibitors of the c-Jun N-terminal kinase.
| S-EPMC2667321 | biostudies-literature

Design, Synthesis and Inhibitory Activity of Photoswitchable RET Kinase Inhibitors.
| S-EPMC4421829 | biostudies-other

Structure-activity relationships and molecular modeling of sphingosine kinase inhibitors.
| S-EPMC3848335 | biostudies-literature

New Quinoxaline Derivatives as Dual Pim-1/2 Kinase Inhibitors: Design, Synthesis and Biological Evaluation.
| S-EPMC7914722 | biostudies-literature

Structure-activity relationship studies and bioactivity evaluation of 1,2,3-triazole containing analogues as a selective sphingosine kinase-2 inhibitors.
| S-EPMC8781238 | biostudies-literature

Design, synthesis, and structure-activity relationship studies of thiophene-3-carboxamide derivatives as dual inhibitors of the c-Jun N-terminal kinase.
| S-EPMC3089059 | biostudies-literature

Design and synthesis of potent, selective inhibitors of matriptase.
| S-EPMC4025795 | biostudies-other