Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic

Sherk, Andrea B.; Frigo, Daniel E.; Schnackenberg, Christine G.; Bray, Jeffrey D.; Laping, Nicholas J.; Trizna, Walter; Hammond, Marlys; Patterson, Jaclyn R.; Thompson, Scott K.; Kazmin, Dmitri; Norris, John D.; McDonnell, Donald P.

doi:10.1158/0008-5472.can-08-1047

Cited by 211Prostate Cancer Treatment and ResearchEstrogen and related hormone effectsUrinary Bladder and Prostate Research

Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic

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Sherk, Andrea B., Frigo, Daniel E., Schnackenberg, Christine G., Bray, Jeffrey D., Laping, Nicholas J., Trizna, Walter, Hammond, Marlys, Patterson, Jaclyn R. +4 more·2008·Cancer Research

DOI 10.1158/0008-5472.can-08-1047PMC PMC2562281

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Abstract

Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we show that the serum and glucocorticoid-regulated kinase 1 (SGK1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional serum- and glucocorticoid-regulated kinase 1 (SGK1) protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNA interference–mediated knockdown of SGK1 expression attenuates the androgen-mediated growth of the prostate cancer cell line LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small-molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR is likely to have therapeutic utility in prostate cancer. [Cancer Res 2008;68(18):7475–83]

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SGK1 inhibitors GSK650394 (100 nM) or EMD638683 (6 μM) reduce Tau phosphorylation at AT8 and S214 sites in AD cortical neurons.
“We treated the 6 lines of cortical neurons with two different SGK1 inhibitors, GSK650394 (GSK, 100 nM) [26] or EMD638683 (6 µM) [27] for 72 h and found marked reduction in the immunostaining of AT8 or S214 phospho-specific antibodies (Figs. 3a–c, S4, S5).”
From Elevated SGK1 increases Tau phosphorylation and microtubule instability in Alzheimer’s patient-derived cortical neurons (2026) · cites this paper as [26]

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Retracted
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Influential
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Lang, F., Artunc, F., & Vallon, V. (2009) · Current Opinion in Nephrology and Hypertension · doi:10.1097/mnh.0b013e32832f125e · Cited by 139 · see citing works
The serum- and glucocorticoid-inducible kinase 1 (SGK1) influences platelet calcium signaling and function by regulation of Orai1 expression in megakaryocytes
Borst, O., Schmidt, E.-M., Münzer, P., Schönberger, T., Towhid, S. T., Elvers, M., Leibrock, C. B., Schmid, E., Eylenstein, A., Kuhl, D., et al. (2011) · Blood · doi:10.1182/blood-2011-06-359976 · Cited by 137 · see citing works
Molecular Mechanisms Underlying Ca2+/Calmodulin-Dependent Protein Kinase Kinase Signal Transduction
Tokumitsu, H., & Sakagami, H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231911025 · Cited by 140 · see citing works
EMD638683, a Novel SGK Inhibitor with Antihypertensive Potency
Ackermann, T. F., Boini, K. M., Beier, N., Scholz, W., Fuchß, T., & Lang, F. (2011) · Cellular Physiology and Biochemistry · doi:10.1159/000331722 · Cited by 121 · see citing works
Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells
Schmidt, S., Liu, G., Liu, G., Yang, W., Honisch, S., Pantelakos, S., Stournaras, C., Hönig, A., & Lang, F. J. W. (2014) · Oncotarget · doi:10.18632/oncotarget.2035 · Cited by 96 · see citing works
INPP4B: the New Kid on the PI3K Block
Agoulnik, I., Hodgson, M., Bowden, W. A., & Ittmann, M. (2011) · OncoTarget · doi:10.18632/oncotarget.260 · Cited by 110 · see citing works
“Expression of both SGK3 and SGK1 is induced by androgens in human prostate cancer cell lines and SGK3 activity may be stimulated by the INPP4B metabolite PI(3)P [18, 20].”
Background
SGK1 inhibition in glia ameliorates pathologies and symptoms in Parkinson disease animal models
Kwon, O., Song, J., Yang, Y., Kim, S., Kim, J. Y., Seok, M., Hwang, I., Yu, J., Karmacharya, J., Maeng, H., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202013076 · Cited by 110 · see citing works
“The specificity of the SGK1 inhibitors has been shown with low levels of cross-reactivity with other members of the AGC Ser/ Thr protein kinase family such as AKT or PDK1(Sherk et al , 2008; Ackermann et al , 2011).”
Transcriptional regulation of core autophagy and lysosomal genes by the androgen receptor promotes prostate cancer progression
Blessing, A. M., Rajapakshe, K., Bollu, L. R., Shi, Y., White, M. A., Pham, A. H., Lin, C., Jonsson, P., Cortés, C. J., Cheung, E. C. W., et al. (2016) · Autophagy · doi:10.1080/15548627.2016.1268300 · Cited by 118 · see citing works
Self-citation
Targeting histone K4 trimethylation for treatment of cognitive and synaptic deficits in mouse models of Alzheimer’s disease
Cao, Q., Wang, W., Williams, J. B., Yang, F., Wang, Z.-J., & Yan, Z. (2020) · Science Advances · doi:10.1126/sciadv.abc8096 · Cited by 108 · see citing works
SGK1 inhibition induces autophagy-dependent apoptosis via the mTOR-Foxo3a pathway
Liu, W., Wang, X., Liu, Z., Wang, Y., Yin, B., Pan, Y., Duan, X., Liao, Z., Chen, Y., Liu, C., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.293 · Cited by 121 · see citing works
“In addition, given the nonspecific inhibitory effects of GSK650394 on other protein kinases, such as SGK2, SGK3 and Akt (Sherk et al, 2008), which we have not investigated in the present study, the possibility that these kinases may also contribute to this difference needs to be further explored.”
BackgroundResultInfluential
Erratum To: The hVps34‐SGK3 pathway alleviates sustained PI3K/Akt inhibition by stimulating mTORC1 and tumour growth
Bago, R., Sommer, E. M., Castel, P., Crafter, C., Bailey, F. P., Shpiro, N., Baselga, J. M., Cross, D. A. E., Eyers, P. A., & Alessi, D. R. (2016) · The EMBO Journal · doi:10.15252/embj.201670010 · Cited by 26 · see citing works
“14h and the other related inhibitors we have analysed (14g, 14i and 14n) are much more specific than a previously reported and widely used SGK inhibitor GSK650394 (Sherk et al , 2008) that inhibits many kinases other than SGK1 (http://www.kinase-screen.mrc.ac.uk/screening-compounds/34880 7?order=field_results_inhibiti…”
SGK1
Cristofano, A. D. (2016) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2016.11.006 · Cited by 101 · see citing works
“The best-known and most used SGK1 inhibitor, GSK650394 (Sherk et al., 2008), has an IC50 of 64 nM for SGK1.”
Influential
Targeting SGK1 in diabetes
Lang, F. J. W., Görlach, A., & Vallon, V. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220903260807 · Cited by 106 · see citing works
“Along those lines, the SGK1 inhibitor GSK650394 has been proposed for anticancer therapy [110].”
Background
Stimulation of Ca 2+ ‐channel Orai1/STIM1 by serum‐and glucocorticoid‐inducible kinase 1 (SGK1)
Eylenstein, A., Gehring, E., Heise, N., Shumilina, E. V., Schmidt, S., Szteyn, K., Münzer, P., Nurbaeva, M. K., Eichenmüller, M., Tyan, L., et al. (2011) · The FASEB Journal · doi:10.1096/fj.10-178210 · Cited by 88 · see citing works
SGK1 in Human Cancer: Emerging Roles and Mechanisms
Sang, Y., Kong, P., Zhang, S., Zhang, L., Cao, Y., Duan, X., Sun, T., Tao, Z., & Liu, W. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.608722 · Cited by 93 · see citing works
“In addition, this inhibitor is only approximately 30-fold more selective for SGK1 than for Akt and other related kinases, such as protein kinase B isoforms (AKT1, AKT2, AKT3), Janus kinase isoforms (JAK1, JAK3), insulin-like growth factor1 receptor (IGF1R), Rho-associated pro te in k inase (ROCK) , dua l - spec ific i…”
BackgroundMethodResultInfluential
Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: the p53 connection
Hasna, J., Hague, F., Rodat-Despoix, L., Geerts, D., Leroy, C., Tulasne, D., Ouadid-Ahidouch, H., & Kischel, P. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-017-0007-1 · Cited by 91 · see citing works
“GSK650394 (known to be a specific Sgk-1 competitive inhibitor [25] was able to Fig.”
Colorectal carcinoma cells—Regulation of survival and growth by SGK1
Lang, F. J. W., Perrotti, N., & Stournaras, C. (2010) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2010.05.016 · Cited by 85 · see citing works
Therapeutic potential of serum and glucocorticoid inducible kinase inhibition
Lang, F. J. W., & Voelkl, J. G. J. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2013.778971 · Cited by 91 · see citing works
“7 SGK1 inhibitors Two small molecule SGK1 inhibitors have been developed, GSK650394A [181] and EMD638683 [182].”
BackgroundInfluential
Androgens Promote Prostate Cancer Cell Growth through Induction of Autophagy
Shi, Y., Han, J. J., Tennakoon, J. B., Mehta, F. F., Merchant, F. A., Burns, A. R., Howe, M. K., McDonnell, D. P., & Frigo, D. E. (2012) · Molecular Endocrinology · doi:10.1210/me.2012-1260 · Cited by 94 · see citing works
Self-citation
RHAMM (CD168) is overexpressed at the protein level and may constitute an immunogenic antigen in advanced prostate cancer disease.
Gust, K., Hofer, M., Perner, S., Kim, R., Chinnaiyan, A., Varambally, S., Møller, P., Rinnab, L., Rubin, M., Greiner, J., et al. (2009) · Neoplasia · doi:10.1593/neo.09694 · Cited by 86 · see citing works
“New therapeutic options such as nucleotid-based targeted therapies, smallmolecule inhibitors [14–17], antiangiogenic agents such as sunitinib [18–21], and novel cytotoxic therapeutics such as satraplatin [8,9,11] were developed that show promise in the management of patients with advanced CaP and are in clinical trial…”
Background
Induction of Krüppel-Like Factor 5 Expression by Androgens Results in Increased CXCR4-Dependent Migration of Prostate Cancer Cellsin Vitro
Frigo, D. E., Sherk, A. B., Wittmann, B. M., Norris, J. D., Wang, Q., Joseph, J. D., Toner, A. P., Brown, M. A., & McDonnell, D. P. (2009) · Molecular Endocrinology · doi:10.1210/me.2009-0010 · Cited by 73 · see citing works
“Stealth siRNA (Invitrogen) transfections were previously described (30).”
BackgroundSelf-citation
Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation
Amato, R., D’Antona, L., Porciatti, G., Agosti, V., Menniti, M., Rinaldo, C., Costa, N., Bellacchio, E., Mattarocci, S., Fuiano, G., et al. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0525-5 · Cited by 103 · see citing works
“Based on these recent observations, Sgk1 antagonistic molecules are considered in the experimental therapy of prostatic cancer [ 14 ], a tumor that is also finally regulated by steroid hormones [15].”
Background
Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader
Tovell, H., Testa, A., Zhou, H., Shpiro, N., Crafter, C., Ciulli, A., & Alessi, D. R. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00505 · Cited by 95 · see citing works
HDAC6 selective inhibition of melanoma patient T-cells augments anti-tumor characteristics
Laino, A. S., Betts, B. C., Veerapathran, A., Dolgalev, I., Sarnaik, A. A., Quayle, S. N., Jones, S. S., Weber, J. S., & Woods, D. M. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0517-0 · Cited by 83 · see citing works
SGK1, the New Player in the Game of Resistance: Chemo-Radio Molecular Target and Strategy for Inhibition
Talarico, C., Dattilo, V., D’Antona, L., Menniti, M., Bianco, C., Ortuso, F., Alcaro, S., Schenone, S., Perrotti, N., & Amato, R. (2016) · Cellular Physiology and Biochemistry · doi:10.1159/000447885 · Cited by 90 · see citing works
Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective TORC2 Activation
Fang, Z., Zhang, T., Dizeyi, N., Chen, S., Wang, H., Swanson, K. D., Cai, C., Balk, S. P., & Yuan, X. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.323303 · Cited by 69 · see citing works
“Interestingly, SGK1 is a direct AR transcriptional target and can stimulate PCa growth (4, 40), although SGK1 protein levels did not increase during the short time courses ofDHT treatment in this study (supplemental Fig.”
Background
The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer
Turnham, D. J., Bullock, N., Dass, M. S., Staffurth, J. N., & Pearson, H. B. (2020) · Cells · doi:10.3390/cells9112342 · Cited by 81 · see citing works
“Significantly, SGK1 inhibition is reported to reduce prostate cancer cell line proliferation and invasive potential, and can synergize with the mTOR inhibitor rapamycin in vitro [256,265].”
Background
Oncogenic Ras differentially regulates metabolism and anoikis in extracellular matrix-detached cells
Mason, J. A., Davison-Versagli, C. A., Leliaert, A. K., Pape, D. J., McCallister, C. M., Zuo, J.-L., Durbin, S., Buchheit, C. L., Zhang, S., & Schafer, Z. T. (2016) · Cell Death and Differentiation · doi:10.1038/cdd.2016.15 · Cited by 72 · see citing works
Regulation of ENaC-mediated alveolar fluid clearance by insulin via PI3K/Akt pathway in LPS-induced acute lung injury
Deng, W., Li, C.-Y., Tong, J., Zhang, W., & Wang, D.-X. (2012) · Respiratory Research · doi:10.1186/1465-9921-13-29 · Cited by 71 · see citing works
“In addtion, co-administration of Akt inhibitor and SGK1 inhibitor, reported to inhibit SGK1 [61], significantly inhibited insulin-induced increase in the expressions of a-, b- and g-ENaC, as well as increased the insulin-induced decrease in the expression of Nedd4-2 compared with administration of Akt inhibitor alone…”
Influential
Serum/glucocorticoid‐regulated kinase 1 expression in primary human prostate cancers
Szmulewitz, R. Z., Chung, E. K., Al‐Ahmadie, H. A., Daniel, S., Kocherginsky, M., Razmaria, A. A., Zagaja, G. P., Brendler, C. B., Stadler, W. M., & Conzen, S. D. (2011) · The Prostate · doi:10.1002/pros.21416 · Cited by 72 · see citing works
“In addition, in vitro studies using small interfering RNAs targeting SGK1 or small molecule pharmacologic inhibitors of SGK1 demonstrate that inhibition of SGK1 activity leads to decreased androgen-mediated prostate cancer cell growth [11,18].”
Background
SGK1 inhibition-induced autophagy impairs prostate cancer metastasis by reversing EMT
Liu, W., Wang, X., Wang, Y., Dai, Y., Xie, Y., Ping, Y., Yin, B., Pan, Y., Liu, Z., Duan, X., et al. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0743-1 · Cited by 74 · see citing works
Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis
Gotoh, S., & Negishi, M. (2015) · Scientific Reports · doi:10.1038/srep14076 · Cited by 65 · see citing works
Inhibition of Colonic Tumor Growth by the Selective SGK Inhibitor EMD638683
Towhid, S. T., Liu, G., Ackermann, T. F., Beier, N., Scholz, W., Fuchß, T., Toulany, M., Rodemann, H. P., & Lang, F. J. W. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000354486 · Cited by 67 · see citing works
SGK3 Is an Estrogen-Inducible Kinase Promoting Estrogen-Mediated Survival of Breast Cancer Cells
Wang, Y.-Z., Zhou, D., Phung, S., Masri, S., Smith, D. D., & Chen, S. (2010) · Molecular Endocrinology · doi:10.1210/me.2010-0294 · Cited by 68 · see citing works
Phosphorylation on the Ser 824 residue of TRPV4 prefers to bind with F-actin than with microtubules to expand the cell surface area
Shin, S. H., Lee, E. J., Hyun, S., Chun, J., Kim, Y., & Kang, S. S. (2012) · Cellular Signalling · doi:10.1016/j.cellsig.2011.11.002 · Cited by 63 · see citing works
The Adherens Junction Protein Afadin is an Akt substrate that Regulates Breast Cancer Cell Migration
Elloul, S., Kedrin, D., Knoblauch, N., Beck, A. H., & Toker, A. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-13-0398 · Cited by 62 · see citing works
Potassium acts through mTOR to regulate its own secretion
Sørensen, M. V., Saha, B., Jensen, I. S., Wu, P., Ayasse, N., Gleason, C. E., Svendsen, S. L., Wang, W., & Pearce, D. (2019) · JCI Insight · doi:10.1172/jci.insight.126910 · Cited by 75 · see citing works
“A role for SGK1 to stimulate ENaC in response to local changes in extracellular [K+] was further supported by the effects of SGK1 inhibition with GSK650394 (27), which blocked the increase in current induced by shifting media [K+] from 1 mM to 5 or 8 mM (Figure 4C) and from 3 mM to 6 mM (Figure 4D).”
BackgroundInfluential
Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4
Castañeda‐Bueno, M., Arroyo, J. P., Zhang, J., Puthumana, J., Yarborough, O. H., Shibata, S., Rojas‐Vega, L., Gamba, G., Rinehart, J., & Lifton, R. P. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1620315114 · Cited by 65 · see citing works
“However, TPA or forskolin-induced increases in WNK4–RRXS phosphorylation were not prevented by SGK1 inhibition with GSK65039 (23), suggesting that these effects were independent of SGK1 (Fig.”
Background
Simulated bladder pressure stimulates human bladder smooth muscle cell proliferation via the PI3K/SGK1 signaling pathway.
Chen, L., Wei, T., Wang, Y., Zhang, J., Li, H., & Wang, K.-J. (2012) · Journal of Urology · doi:10.1016/j.juro.2012.03.112 · Cited by 57
The activity of the androgen receptor variant AR‐V7 is regulated by FOXO1 in a PTEN‐PI3K‐AKT‐dependent way
Mediwala, S. N., Sun, H., Szafran, A. T., Hartig, S. M., Sonpavde, G., Hayes, T. G., Thiagarajan, P., Mancini, M. A., & Marcelli, M. (2012) · The Prostate · doi:10.1002/pros.22566 · Cited by 54 · see citing works
“Inhibition of Janus kinase 2 (JAK2) by AG490 or serine/threonine-protein kinase (SGK) by GSK650394 [16] had no effect on AR-V7-dependent relative luciferase activity.”
Background
SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation
D'Antona, L., Amato, R., Talarico, C., Ortuso, F., Menniti, M., Dattilo, V., Iuliano, R., Gigliotti, F., Artese, A., Costa, G., et al. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000374008 · Cited by 55 · see citing works
PDK1 and SGK3 contribute to the growth of BRAF mutant melanomas and are potential therapeutic targets
Scortegagna, M., Lau, E., Zhang, T.-W., Feng, Y.-M., Sereduk, C., Yin, H.-W., De, S., Meeth, K., Platt, J., Langdon, C., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2785 · Cited by 53 · see citing works
“To this end, we treated the Braf::Cdkn2a / ::Pten / and Braf::Cdkn2a / ::Ptenþ/þ cell cultures with either the SGK inhibitor (SGKi)GSK650394 (21) or the PDK1 inhibitor (PDK1i) GSK2334470 (22) for 24 hours and then examined PDK1-dependent signaling pathway components.”
Method
The prospect of serum and glucocorticoid-inducible kinase 1 (SGK1) in cancer therapy: a rising star
Zhu, R., Yang, G., Cao, Z., Shen, K., Zheng, L., Xiao, J., You, L., & Zhang, T. (2020) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758835920940946 · Cited by 58 · see citing works
The role of Sgk-1 in the upregulation of transport proteins by PPAR-{gamma} agonists in human proximal tubule cells.
Saad, S., Agapiou, D., Chen, X.-M., Stevens, V. A., & Pollock, C. (2008) · Nephrology, Dialysis and Transplantation · doi:10.1093/ndt/gfn614 · Cited by 51 · see citing works
“To determine the role of Sgk in mediating observed changes, a recently synthesized Sgk inhibitor (GSK650394A) was used [26].”
Method
Pharmacological reactivation of inactive X-linked Mecp2 in cerebral cortical neurons of living mice
Przanowski, P., Waśko, U., Zheng, Z.-T., Yu, J., Sherman, R., Zhu, L., McConnell, M. J., Tushir-Singh, J., Green, M. R., & Bhatnagar, S. (2018) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1803792115 · Cited by 49
Salt Sensing by Serum/Glucocorticoid-Regulated Kinase 1 Promotes Th17-like Inflammatory Adaptation of Foxp3+ Regulatory T Cells
Yang, Y. H., Istomine, R., Alvarez, F., Al-Aubodah, T.-A., Shi, X., Takano, T., Thornton, A. M., Shevach, E. M., Zhang, J., & Piccirillo, C. A. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.002 · Cited by 57 · see citing works
“…and Foxp3 + tTreg cells in the presence of salt and in the presence or absence of a SGK1-specific pharmacological inhibitor (SGK1i; GSK650394) at a concentration at which no toxic effect is observed, all the while abrogating SGK1 kinase activity (Sherk et al., 2008; Kleinewietfeld et al., 2013).”
Selective glucocorticoid receptor modulators (SGRMs) delay castrate-resistant prostate cancer growth
Kach, J., Long, T., Selman, P., Tonsing-Carter, E., Bacalao, M. A., Lastra, R., de Wet, L., Comiskey, S., Gillard, M., VanOpstall, C., et al. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0923 · Cited by 48 · see citing works
“The putative AR/GR target genes SGK1 andKLK3were selected for their established roles in CRPC; SGK1 independently confers castration-resistant progression (11, 34), and KLK3/PSA is a commonly used serum biomarker associated with CRPC progression.”
Background
Increased intracellular Cl− concentration promotes ongoing inflammation in airway epithelium
Zhang, Y., Chen, P.-X., Guan, W., Guo, H., Qiu, Z.-E., Xu, J., Luo, Y.-L., Lan, C.-F., Xu, J.-B., Hao, Y. T., et al. (2018) · Mucosal Immunology · doi:10.1038/s41385-018-0013-8 · Cited by 53 · see citing works
Spinal SGK1/GRASP-1/Rab4 is involved in complete Freund’s adjuvant-induced inflammatory pain via regulating dorsal horn GluR1-containing AMPA receptor trafficking in rats
Peng, H., Chen, G., Hsieh, M., Lai, C., Huang, Y., & Lin, T.-B. (2012) · Pain · doi:10.1016/j.pain.2012.08.004 · Cited by 47 · see citing works
“]; Tocris, Minneapolis, MN, USA), a selective SGK1 inhibitor (with IC50 of 62 and 103 nM for SGK1 and SGK2, respectively, and displays more than 30-fold selectivity over Akt and other related kinase) [29], and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1, 30, 10 lM, 10 lL, i.”
Background
Serum and glucocorticoid-regulated kinase 1 (SGK1) activation in breast cancer: Requirement for mTORC1 activity associates with ER-alpha expression
Hall, B. A., Kim, T., Skor, M. N., & Conzen, S. (2012) · Breast Cancer Research and Treatment · doi:10.1007/s10549-012-2161-y · Cited by 46 · see citing works
“the growth of both prostate and cervical cancer cells [25].”
Background
Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model
Zhang, D., Yu, W., Liu, J., Kong, L., Zhang, N., Song, Y., Li, X., Fan, Z., Lyu, Y., Li, N., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36949-4 · Cited by 47 · see citing works
Therapeutic inhibition of SGK1 suppresses colorectal cancer
Liang, X., Lan, C. B., Jiao, G., Fu, W., Long, X., An, Y., Wang, K., Zhou, J., Chen, T., Li, Y., et al. (2017) · Experimental & Molecular Medicine · doi:10.1038/emm.2017.184 · Cited by 58 · see citing works
Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors.
Hammond, M., Washburn, D., Hoang, H. T., Manns, S., Frazee, J., Nakamura, H., Patterson, J. R., Trizna, W., Wu, C. W., Azzarano, L. M., et al. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.05.051 · Cited by 43
Self-citation
Aurora B Inhibitors as Cancer Therapeutics
Kovacs, A. H., Zhao, D.-J., & Hou, J.-Q. (2023) · Molecules · doi:10.3390/molecules28083385 · Cited by 39
SGK1, a Critical Regulator of Immune Modulation and Fibrosis and a Potential Therapeutic Target in Chronic Graft-Versus-Host Disease
Lu, R., Zhang, Y., Zhao, H., Guo, R., Jiang, Z., & Guo, R. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.822303 · Cited by 35 · see citing works
“GSK650394 has been shown to delay cancer progression by inhibiting cell growth and inducing apoptosis in prostate cancer cells (49, 51, 52).”
Background
Use of LC-MS/MS and Bayes' theorem to identify protein kinases that phosphorylate aquaporin-2 at Ser256.
Bradford, D., Raghuram, V., Wilson, J. L. L., Chou, C.-L., Hoffert, J., Knepper, M., & Pisitkun, T. (2014) · American Journal of Physiology - Cell Physiology · doi:10.1152/ajpcell.00377.2012 · Cited by 39
“The IMCD suspensions were preincubated for 25 min with one of the following protein kinase inhibitors (or their vehicles): H-89, a relatively nonselective inhibitor of basophilic kinases (7) (Calbiochem, San Diego, CA); KN-62, a CAMK2-selective inhibitor (58) (Calbiochem); KN-93, a CAMK2-selective inhibitor (58) (Calb…”
Serum‐ and glucocorticoid‐dependent kinase‐1‐induced cell migration is dependent on vinculin and regulated by the membrane androgen receptor
Schmidt, E., Gu, S., Anagnostopoulou, V., Alevizopoulos, K., Föller, M., Lang, F. J. W., & Stournaras, C. (2012) · FEBS Journal · doi:10.1111/j.1742-4658.2012.08515.x · Cited by 36 · see citing works
Hepatocyte SGK1 activated by hepatic ischemia-reperfusion promotes the recurrence of liver metastasis via IL-6/STAT3
Li, X.-D., Wang, Z.-Y., Jiao, C.-Y., Zhang, Y., Xia, N., Yu, W.-J., Chen, X.-J., Wikana, L. P., Liu, Y., Sun, L., et al. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-03977-z · Cited by 38 · see citing works
Serum and glucocorticoid inducible protein kinases (SGKs): a potential target for cancer intervention
Basnet, R., Gong, G. Q., Li, C., & Wang, M. (2018) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2018.07.001 · Cited by 46 · see citing works
Effects of nominally selective inhibitors of the kinases PI3K, SGK1 and PKB on the insulin‐dependent control of epithelial Na+ absorption
Mansley, M. K., & Wilson, S. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00898.x · Cited by 37 · see citing works
“…cells were acutely exposed to GSK650394A (1–10 mM, added to 578 British Journal of Pharmacology (2010) 161 571–588 the apical and basolateral baths), an inhibitor of SGK1 (Sherk et al., 2008), showed that this compound had no significant effect upon the IEq when used at 1 mM and 3 mM (Figure 5A).”
BackgroundMethodInfluential
Serum and glucocorticoid-regulated kinase 1: Structure, biological functions, and its inhibitors
Jang, H., Park, Y. J., & Jang, J. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1036844 · Cited by 43 · see citing works
“Compound (original code) Structure SGK1 inhibition Target disease tested Biological effect Ref 1 (EMD638683) 15% residual SGK1 activity at 1 µM Hypertension/ Inflammation ■ IC50 = 3.35 ± 0.32 µM (HeLa cells, p-NDRG1) Sherk et al. (2008) ■ Blood pressure = (HeLa cells, p-NDRG1) Ackermann et al. (2011) 2 (5377051) IC50…”
BackgroundInfluential
In Silico Identification and Biological Evaluation of Novel Selective Serum/Glucocorticoid-Inducible Kinase 1 Inhibitors Based on the Pyrazolo-Pyrimidine Scaffold
Ortuso, F., Amato, R., Artese, A., D’Antona, L., Costa, G., Talarico, C., Gigliotti, F., Bianco, C., Trapasso, F., Schenone, S., et al. (2014) · Journal of Chemical Information and Modeling · doi:10.1021/ci500235f · Cited by 37 · see citing works
Insights Into the Biological Role of NEDD4L E3 Ubiquitin Ligase in Human Cancers
Xie, S.-D., Xia, L., Song, Y., Liu, H.-J., Wang, Z.-W., & Zhu, X.-Q. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.774648 · Cited by 35
“Interestingly, the expression of three NEDD4L transcripts, NEDD4Lf, NEDD4Lg and NEDD4Lh, was upregulated in prostate cancer cells after androgen administration (68, 69).”
Background
SGK3 is an androgen-inducible kinase promoting prostate cancer cell proliferation through activation of p70 S6 kinase and up-regulation of cyclin D1.
Wang, Y.-Z., Zhou, D.-J., & Chen, S. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1339 · Cited by 35 · see citing works
Small molecule LATS kinase inhibitors block the Hippo signaling pathway and promote cell growth under 3D culture conditions
Aihara, A., Iwawaki, T., Abe‐Fukasawa, N., Otsuka, K., Saruhashi, K., Mikashima, T., & Nishino, T. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.101779 · Cited by 43 · see citing works
Epithelial Sodium Channel Regulation by Cell Surface-associated Serum- and Glucocorticoid-regulated Kinase 1
Thomas, S. V., Kathpalia, P. P., Rajagopal, M., Charlton, C. A., Zhang, J., Eaton, D. C., Helms, M. N., & Pao, A. C. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.278283 · Cited by 33 · see citing works
Inhibition of SGK1 confers vulnerability to redox dysregulation in cervical cancer
Wang, M., Xue, Y., Shen, L., Qin, P., Sang, X., Tao, Z., Yi, J., Wang, J., Liu, P.-X., & Cheng, H.-L. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101225 · Cited by 33 · see citing works
“Next, we tested the impact of GSK650394, a selective SGK1 inhibitor [23,30], on ROS homeostasis.”
BackgroundMethod
SGK3 sustains ERα signaling and drives acquired aromatase inhibitor resistance through maintaining endoplasmic reticulum homeostasis
Wang, Y.-Z., Zhou, D., Phung, S., Warden, C., Rashid, R., Chan, N., & Chen, S. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612991114 · Cited by 31 · see citing works
“GSK650394 is a pan-SGK inhibitor and blocks SGK1 activity in the nanomolar range, but inhibits SGK3 activity at higher concentrations (18).”
Background
SGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-α
Pastore, D., Della-Morte, D., Coppola, A., Capuani, B., Lombardo, M., Pacifici, F., Ferrelli, F., Arriga, R., Mammi, C., Federici, M., et al. (2015) · Cell Death and Disease · doi:10.1038/cddis.2015.232 · Cited by 33 · see citing works
“To test whether SGK-1 is pivotal in the protection against apoptosis induced by ceramide, we treated the three groups with a selective inhibitor of SGK-1 activity (GSK650394) 60min before TNF-α stimulation.(30) After 72 h, cells were analysed by FACS (Supplementary Figure S1).”
Method
Validation of histone deacetylase 3 as a therapeutic target in castration‐resistant prostate cancer
McLeod, A., Stice, J. P., Wardell, S., Alley, H. M., Chang, C.-Y., & McDonnell, D. (2018) · The Prostate · doi:10.1002/pros.23467 · Cited by 32 · see citing works
Self-citation
Role of SGK1 for fatty acid uptake, cell survival and radioresistance of NCI-H460 lung cancer cells exposed to acute or chronic cycling severe hypoxia
Matschke, J., Wiebeck, E., Hurst, S., Rudner, J., & Jendrossek, V. (2016) · Radiation Oncology · doi:10.1186/s13014-016-0647-1 · Cited by 31 · see citing works
“We chose a concentration of 40 μM on the basis of LC50 values of 40 to 100 μM obtained in cell-based in vitro assays by others [41].”
Method
Roles of Akt and SGK1 in the Regulation of Renal Tubular Transport
Satoh, N., Nakamura, M., Suzuki, M., Suzuki, A., Seki, G., & Horita, S. (2015) · BioMed Research International · doi:10.1155/2015/971697 · Cited by 36 · see citing works
Curcumin and Carnosic Acid Cooperate to Inhibit Proliferation and Alter Mitochondrial Function of Metastatic Prostate Cancer Cells
Ossikbayeva, S., Khanin, M., Sharoni, Y., Trachtenberg, A., Tuleukhanov, S., Sensenig, R., Rom, S., Danilenko, M., & Orynbayeva, Z. (2021) · Antioxidants · doi:10.3390/antiox10101591 · Cited by 30 · see citing works
“In prostate cancer, SGK1 inhibition also has anti-androgen effects [97].”
Background
Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp12/7/8 RNA-dependent RNA polymerase
Bertolin, A. P., Weissmann, F., Zeng, J.-K., Posse, V., Milligan, J. C., Canal, B., Ulferts, R., Wu, M. Y., Drury, L. S., Howell, M., et al. (2021) · bioRxiv · doi:10.1042/bcj20210200 · Cited by 30 · see citing works
“GSK-650394 is an inhibitor of SGK-1 kinase (68) that plays an important role in a diverse range of cellular processes such as stress response, ion transport, inflammation and cell proliferation (69).”
Background
Development and exploitation of a novel mutant androgen receptor modelling strategy to identify new targets for advanced prostate cancer therapy
O’Neill, D. J., Jones, D. L., Wade, M., Grey, J., Nakjang, S., Guo, W., Cork, D. M. W., Davies, B. R., Wedge, S. R., Robson, C. N., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.4347 · Cited by 30 · see citing works
SGK-1 regulates inflammation and cell death in the ischemic-reperfused heart: pressure-related effects.
Baban, B., Liu, J.-Y., & Mozaffari, M. (2014) · American Journal of Hypertension · doi:10.1093/ajh/hpt269 · Cited by 28 · see citing works
Role of serum‐ and glucocorticoid‐inducible kinases in stroke
Inoue, K., Leng, T., Yang, T., Zeng, Z., Ueki, T., & Xiong, Z. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13650 · Cited by 30 · see citing works
Identification of a Novel Coregulator, SH3YL1, That Interacts With the Androgen Receptor N-Terminus.
Blessing, A., Ganesan, S., Rajapakshe, K., Sung, Y., Bollu, L. R., Shi, Y., Cheung, E., Coarfa, C., Chang, J. T., McDonnell, D., et al. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1079 · Cited by 27
Self-citation
SGK1 inhibits PM2.5-induced apoptosis and oxidative stress in human lung alveolar epithelial A549 cells.
Li, J., Zhou, Q.-L., Yang, T.-T., Li, Y., Zhang, Y.-H., Wang, J.-H., & Jiao, Z. (2018) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2018.02.002 · Cited by 26 · see citing works
Activation of 3-Phosphoinositide-dependent Kinase 1 (PDK1) and Serum- and Glucocorticoid-induced Protein Kinase 1 (SGK1) by Short-chain Sphingolipid C4-ceramide Rescues the Trafficking Defect of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR)*
Caohuy, H., Yang, Q., Eudy, Y., Ha, T.-A., Xu, A., Glover, M. L., Frizzell, R., Jozwik, C., & Pollard, H. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.598649 · Cited by 25 · see citing works
“9A also shows that when the incubation includes either PDK1 inhibitor GSK2334470 or SGK1 inhibitor GSK650394, Nedd4-2 is not phosphorylated.”
BackgroundMethodInfluential
Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes
Eduful, B. J., O’Byrne, S. N., Temme, L., Asquith, C. R. M., Liang, Y., Picado, A., Pilotte, J. R., Hossain, M. A., Wells, C. I., Zuercher, W. J., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02274 · Cited by 33 · see citing works
Self-citation
Serum- and Glucocorticoid-Regulated Kinase 1 Is Required for Nuclear Export of the Ribonucleoprotein of Influenza A Virus
Alamares-Sapuay, J. G., Martínez-Gil, L., Stertz, S., Miller, M. S., Shaw, M., & Palese, P. (2013) · Journal of Virology · doi:10.1128/jvi.01258-12 · Cited by 24
“In the absence of androgens, GSK 650394 was not toxic to LNCaP cells (21).”
Background
NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor
Zhang, M., Zhang, Z.-Y., Tian, X., Zhang, E.-C., Wang, Y., Tang, J., & Zhao, J.-Z. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1291773 · Cited by 23 · see citing works
Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer
Jayaprakash, S., Hegde, M., BharathwajChetty, B., Girisa, S., Alqahtani, M. S., Abbas, M. A. E., Sethi, G., & Kunnumakkara, A. B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012380 · Cited by 27 · see citing works
Serum- and glucocorticoid-induced kinase 1, a new therapeutic target for autophagy modulation in chronic diseases
Maestro, I., Boya, P., & Martı́nez, A. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1730328 · Cited by 22 · see citing works
“GSK650934 shows over 30-fold higher selectivity for SGK1 than Akt and other related kinases and can inhibit androgen-stimulated growth of human prostate carcinoma LNCaP cells with an IC50 value of approximately 1 μM [106].”
Background

Authors: Sherk, A. B., Frigo, D. E., Schnackenberg, C. G., Bray, J. D., Laping, N. J., Trizna, W., Hammond, M., Patterson, J. R., Thompson, S. K., Kazmin, D., Norris, J. D., & McDonnell, D. P.
Affiliations: Duke Medical Center (US)
Houston Methodist (US)
GlaxoSmithKline (United States) (US)
ORCID: Frigo, Daniel E.
Patterson, Jaclyn R.
Kazmin, Dmitri
Norris, John D.
McDonnell, Donald P.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2008-09-14
Volume: 68
Issue: 18
Pages: 7475-7483
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-08-1047
PMC: PMC2562281
OpenAlex: W2127577957
Cited by: 211
References: 41
Citations by year: 2026: 11 · 2025: 9 · 2024: 7 · 2023: 12 · 2022: 19 · 2021: 20 · 2020: 17 · 2019: 10 · 2018: 12 · 2017: 12 · 2016: 13 · 2015: 12 · 2014: 14 · 2013: 8 · 2012: 9
FWCI: 8.26
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: U.S. Department of Defense
GlaxoSmithKline
University of Dundee
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney Diseases (F32DK072794, R01DK065251)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Health Sciences › Medicine › Urology › Urinary Bladder and Prostate Research
Keywords: SGK1, prostate cancer, androgen receptor, androgen signaling, Nedd4-2, small-molecule kinase inhibitors, LNCaP cells, androgen deprivation therapy
MeSH terms: Serum-Glucocorticoid Regulated Kinases, Benzoates, HeLa Cells, Humans, Male, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Metribolone, Up-Regulation, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Bridged Bicyclo Compounds, Heterocyclic, RNA, Small Interfering, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Growth Processes

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Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic

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