| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T94479 | ||||
| Target Name | Ribosomal protein S6 kinase | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol | Drug Info | IC50 = 10000 nM | [528490] | |
| PHA-767491 | Drug Info | IC50 = 3010 nM | [528819] | ||
| BISINDOLYLMALEIMIDE IX | Drug Info | IC50 = 8 nM | [525872] | ||
| SB-747651A | Drug Info | IC50 = 0.5 nM | [527594] | ||
| Action against Disease Model | XL418 | XL418 potently inhibits the activity of AKT and S6K in preclinical models, reducing t uMor growth and enhancing the effects of other targeted therapies. XL418 slowed t uMor growth in multiple cancer models, including breast and lung adenocarcinomas. XL418 also has been shown to enhance apoptosis in combination with XL647, an inhibitor of multiple receptor tyrosine kinases including EGFR, HER2, and VEGFR, in preclinical t uMor models. | Drug Info | ||
| The Effect of Target Knockout, Knockdown or Genetic Variations | In the present study, we report that deletion of S6 kinase 1 (S6K1) inhibited renal hypertrophy seen following either contralateral nephrectomy or induction of diabetes. In wild-type mice, hypertrophic stimuli increased phosphorylation of 40S ribosomal protein S6 (rpS6), a known target of S6K1. Immunoblotting analysis revealed that S6K1(-/-) mice exhibited moderately elevated basal levels of rpS6, which did not increase further in response to the hypertrophic stimuli. Northern blotting indicated a moderate upregulation of S6K2 expression in the kidneys of S6K1(-/-) mice.Phosphorylation of the eukaryotic translation initiation factor 4E-binding protein 1, another downstream target of the mammalian target of rapamycin (mTOR), was stimulated to equivalent levels in S6K1(-/-) and S6K1(+/+) littermates during renal hypertrophy, indicating that mTOR was still activated in the S6K1(-/-) mice. The highly selective mTOR inhibitor, rapamycin, inhibited increased phosphorylation of rpS6 and blocked 60-70% of the hypertrophy seen in wild-type mice but failed to prevent the approximately 10% hypertrophy seen in S6K1(-/-) mice in response to uninephrectomy (UNX) although it did inhibit the basal rpS6 phosphorylation. Thus the present study provides the first genetic evidence that S6K1 plays a major role in the development of compensatory renal hypertrophy as well as diabetic renal hypertrophy and indicates that UNX- and diabetes-mediated mTOR activation can selectively activate S6K1 without activating S6K2 | ||||
| References | |||||
| Ref 528490 | J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. | ||||
| Ref 528819 | J Med Chem. 2007 May 31;50(11):2647-54. Epub 2007 May 5.Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). | ||||
| Ref 525872 | Biochem J. 2000 Oct 1;351(Pt 1):95-105.Specificity and mechanism of action of some commonly used protein kinase inhibitors. | ||||
| Ref 527594 | Bioorg Med Chem Lett. 2005 Jul 15;15(14):3407-11.(1H-imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: further optimisation as highly potent and selective MSK-1-inhibitors. | ||||
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