In Silico Identification and Biological Evaluation of Novel Selective Serum/Glucocorticoid-Inducible Kinase 1 Inhibitors Based on the Pyrazolo-Pyrimidine Scaffold

Ortuso, Francesco; Amato, Rosario; Artese, Anna; D’Antona, Lucia; Costa, Giosuè; Talarico, Cristina; Gigliotti, Francesco; Bianco, Cataldo; Trapasso, Francesco; Schenone, Silvia; Musumeci, Francesca; Botta, Lorenzo; Perrotti, Nicola; Alcaro, Stefano

doi:10.1021/ci500235f

Cited by 35 publications

(57 citation statements)

References 31 publications

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“…The data reported here provide an improved characterization, at a molecular and cellular level, of the SI113 Sgk1 inhibitor previously described by our group [30]. Indeed, this molecule appears effective and selective in inhibiting Sgk1 kinase activity, either evaluating its efficacy using isolated (recombinant or endogenous) proteins in specific kinase assays, or employing Mdm2 as a surrogate marker for Sgk1 kinase activity in an intact cellular environment (RKO cells).…”

Section: Discussionmentioning

confidence: 82%

“…Active Sgk1, Akt1, Abl, and Src kinases (all by EMD Millipore, Darmstadt, Germany) were incubated in the appropriate kinase buffers provided by the manufacturer in the absence or in the presence of specific target peptides, as indicated in the Results section, according to previously published methods [30]. The reactions were allowed to occur for 30 min at room temperature, with gentle agitation, prior to adding 10 ml of stopping solution (1 mM ATP, 2%bovine serum albumin, 0.6% w/v HCl).…”

Section: Methodsmentioning

confidence: 99%

“…One of these molecules, compound 3 (henceforth SI113), was particularly effective in inhibiting Sgk1 kinase activity, being much less effective on Akt1 activity, probably because it fits better with the lipophilic area of the ATP binding domain that in Sgk1 is larger than in Akt1 [30]. The structural formula of SI113 is shown in Fig.…”

Section: Introductionmentioning

confidence: 99%

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SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

D’Antona

Amato

Talarico

et al. 2015

Cell Physiol Biochem

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Background/Aims:Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes. Methods:By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1. Results: SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of p53 protein stability, and induced necrosis and apoptosis when used as a single agent. Finally, SI113 potentiated the effects of paclitaxel on cell viability. Conclusion:Since SI113 appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity, we believe that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy.

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Section: Discussionmentioning

confidence: 82%

Section: Methodsmentioning

confidence: 99%

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SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

D’Antona

Amato

Talarico

et al. 2015

Cell Physiol Biochem

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“…A limited number of inhibitors of SGK1 have been described in the literature so far including the azaindoles 1 and 2, the hydrazides 3 and 4, and their 3-aminoindazole isosteres 5 and 6 as shown in Figure 1. 22 Cocrystal structures of ligands 1 and 2 in the SGK1 enzyme supported a bidentate interaction of the ligand scaffold with the kinase hinge region.…”

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confidence: 95%

Discovery of N-[4-(1H-Pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides as Highly Active and Selective SGK1 Inhibitors

Halland

Schmidt

Weiß

et al. 2014

ACS Med. Chem. Lett.

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From a virtual screening starting point, inhibitors of the serum and glucocorticoid regulated kinase 1 were developed through a combination of classical medicinal chemistry and library approaches. This resulted in highly active small molecules with nanomolar activity and a good overall in vitro and ADME profile. Furthermore, the compounds exhibited unusually high kinase and off-target selectivity due to their rigid structure. KEYWORDS: Serum glucocorticoid regulated kinase, WNT signaling, AGC kinase, virtual screening T he serum and glucocorticoid regulated kinase 1 (SGK1) belongs to the serine/threonine kinase family (AGC kinases) and is an important downstream effector in the phosphatidylinositol-3-kinase pathway. SGK1 regulates transport, hormone release, cell proliferation, and apoptosis.1,2 There is a strong body of evidence that dysfunction or dysregulation of SGK1 is involved in many pathological conditions ranging from cancer, hypertension, diabetes, and thrombotic events to neurodegeneration.3−6 Albeit ubiquitously expressed, the transcription is highly regulated and stimulated by physiological events like hyperglycaemia, cell shrinkage, ischemia, glucocorticoids, mineralocorticoids, and insulin as well as by inflammatory mediators including TGFβ. SGK1 regulates several ion channels such as ENaC, KCNE1/KCNQ1, carriers like NCC, NHE3, SGLT1, Na(+)/K(+)-ATPase, and transcription factors including FOXO3a, NF-κβ, and β-catenin.7−11 Recently, it was shown that β-catenin phosphorylation by SGK1 mediates the crosstalk between the corticoid-and WNT-signaling pathways. 7,12,13 Surprisingly, despite the highly relevant, validated biological function of SGK1 only a few inhibitors with appropriate selectivity and potency for the selective interference with SGK1 have been described so far.14−17 Here we report the identification and optimization of highly active and selective SGK1 inhibitors as chemical tools for the further elucidation and validation of the biological role of SGK1. 18Computational screening, particularly 3D ligand-based virtual screening technologies, have emerged as efficient methods for the discovery of novel drug candidates.19−21 Ligand-based virtual screening uses known active molecules to identify new ligands sharing a set of relevant molecular properties such as molecular shape and electrostatics. A limited number of inhibitors of SGK1 have been described in the literature so far including the azaindoles 1 and 2, the hydrazides 3 and 4, and their 3-aminoindazole isosteres 5 and 6 as shown in Figure 1. 22Cocrystal structures of ligands 1 and 2 in the SGK1 enzyme supported a bidentate interaction of the ligand scaffold with the kinase hinge region.14 Using a docking model 23 a bidentate hinge interaction of the para-phenolic substituent was also assumed for 3 and 4 as well as a tridentate interaction for compounds 5 and 6

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“…SGK1 also affects mitotic stability and miRNAs nuclear transport and maturation by regulating RANBP1 and RANGAP1, the pivotal regulators of the GTPase RAN [32,33]. Recently, we found a family of dual SRC/ABL small molecule inhibitors, characterized by a substituted pyrazolo [3,4-d]pyrimidine scaffold, able to inhibit SGK1 and AKT kinase activity [34]. Among these molecules, SI113 has been demonstrated to inhibit SGK1 activity, while being much less effective on AKT1, ABL and SRC [35].…”

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confidence: 99%

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

Catalogna

Talarico

Dattilo

et al. 2017

Cell Physiol Biochem

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Background/Aims: The importance of copper in the metabolism of cancer cells has been widely studied in the last 20 years and a clear-cut association between copper levels and cancer deregulation has been established. Copper-64, emitting positrons and β-radiations, is indicated for the labeling of a large number of molecules suitable for radionuclide imaging as well as radionuclide therapy. Glioblastoma multiforme (GBM) is the CNS tumor with the worse prognosis, characterized by high number of recurrences and strong resistance to chemo-radio therapy, strongly affecting patients survival. We have recently discovered and studied the small molecule SI113, as inhibitor of SGK1, a serine/threonine protein kinase, that affects several neoplastic phenotypes and signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation, perturbs cell cycle progression and restores chemoradio sensibility by modulating SGK1-related substrates. In the present paper we aim to characterize the combined effects of 64 CuCl 2 and SI113 on human GBM cell lines with variable p53 expression. Methods: Cell viability, cell death and stress/authopagic related pathways were then analyzed by FACS and WB-based assays, after exposure to SI113 and/or 64 CuCl 2 . Results: We demonstrate here, that i) 64 CuCl 2 is able to induce a time and dose dependent modulation of cell viability (with different IC 50 values) in highly malignant gliomas and that the co-treatment with SI113 leads to ii) additive/synergistic effects in terms of cell death; iii) enhancement of the effects of ionizing radiations, probably by a TRC1 modulation; iv) modulation of the autophagic response. Conclusions: Evidence reported here underlines the therapeutic potential of the combined treatment with SI113 and 64 CuCl 2 in GBM cells.G. Catalogna and C. Talarico equally contributed to this work.

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In Silico Identification and Biological Evaluation of Novel Selective Serum/Glucocorticoid-Inducible Kinase 1 Inhibitors Based on the Pyrazolo-Pyrimidine Scaffold

Cited by 35 publications

References 31 publications

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

Discovery of N-[4-(1H-Pyrazolo[3,4-b]pyrazin-6-yl)-phenyl]-sulfonamides as Highly Active and Selective SGK1 Inhibitors

The SGK1 Kinase Inhibitor SI113 Sensitizes Theranostic Effects of the 64CuCl2 in Human Glioblastoma Multiforme Cells

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