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Development of a Small-Molecule Serum- and Glucocorticoid-Regulated Kinase-1 Antagonist and Its Evaluation as a Prostate Cancer Therapeutic
Open accessPublished version of a preprint
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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“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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“Specifically, upon PI3K activation, SGK1 is phosphorylated at Ser 422 by an as yet unidentified kinase, referred to as the phosphoinositide-dependent protein kinase (PDK)-2, followed by the phosphorylation of Thr 256 within the activation loop of the SGK1 catalytic domain by PDK1 to become fully activated (19).”
InfluentialBolla, M., Collette, L., Blank, L., Warde, P., Dubois, J. B., Mirimanoff, R.-O., Storme, G., Bernier, J., Kuten, A., Sternberg, C., et al. (2002) · The Lancet · doi:10.1016/s0140-6736(02)09408-4 · Cited by 1,686 · cited 1×
“Although 80% of patients with local or metastatic prostate cancer initially respond favorably to androgen ablation therapy, most patients eventually experience a relapse of the disease, which is then considered to be hormone refractory (2, 3).”
Molecular Mechanisms of Human Hypertension
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“Specifically, upon PI3K activation, SGK1 is phosphorylated at Ser(422) by an as yet unidentified kinase, referred to as the phosphoinositide-dependent protein kinase (PDK)-2, followed by the phosphorylation of Thr(256) within the activation loop of the SGK1 catalytic domain by PDK1 to become fully activated (19).”
Park, J., Leong, M., Buse, P., Maiyar, A. C., Firestone, G. L., & Hemmings, B. (1999) · EMBO Journal · doi:10.1093/emboj/18.11.3024 · Cited by 588
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“Whereas SGK1 and SGK3 have been shown to phosphorylate many of the same target proteins in vitro , differences in subcellular localization suggest that these proteins regulate distinct signaling pathways (36).”
Lawton, C., Winter, K., Murray, K., Machtay, M., Mesic, J., Hanks, G., Coughlin, C. T., & Pilepich, M. (2001) · International Journal of Radiation Oncology, Biology, Physics · doi:10.1016/s0360-3016(00)01516-9 · Cited by 386 · cited 1×
“Although 80% of patients with local or metastatic prostate cancer initially respond favorably to androgen ablation therapy, most patients eventually experience a relapse of the disease, which is then considered to be hormone refractory (2, 3).”
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Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells
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The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis
Massie, C. E., Lynch, A., Ramos‐Montoya, A., Boren, J., Stark, R., Fazli, L., Warren, A., Scott, H., Madhu, B., Sharma, N., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.158 · Cited by 624
“…prostate cancer (e.g., WWP1, ERBB2, MEK5, SGK1 and IGF1R) (Figure 2C; Craft et al, 1999; Hellawell et al, 2002; Mehta et al, 2003; Chen et al, 2007; Sherk et al, 2008), the combined analysis of direct AR targets and androgen-regulated genes also revealed a significant enrichment of metabolic…”
BackgroundPI3K signaling in cancer: beyond AKT
Lien, E. C., Dibble, C. C., & Toker, A. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.02.007 · Cited by 453
Anacker, C., Cattaneo, A., Musaelyan, K., Zunszain, P. A., Horowitz, M., Molteni, R., Luoni, A., Calabrese, F., Tansey, K., Gennarelli, M., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300886110 · Cited by 319
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“Some pieces of evidence suggest that various ATP-competitive inhibitors lack selectivity for all SGK isoforms, as they share similar affinity for different isoforms [87, 88].”
BackgroundIsikbay, M., Otto, K. B., Kregel, S., Kach, J., Cai, Y., Griend, D. J. V., Conzen, S. D., & Szmulewitz, R. Z. (2014) · Hormones and Cancer · doi:10.1007/s12672-014-0173-2 · Cited by 273
“In models of human PC, increased SGK1 expression facilitates AR-regulated cell survival, and in breast cancer, SGK1 expression confers relat ive resistance to chemotherapy-induced cell death [36, 37, 47].”
The Homeodomain Protein HOXB13 Regulates the Cellular Response to Androgens
Norris, J., Chang, C.-Y., Wittmann, B. M., Kunder, R., Cui, H.-X. N., Fan, D.-J., Joseph, J., & McDonnell, D. (2009) · Molecules and Cells · doi:10.1016/j.molcel.2009.10.020 · Cited by 227
“Furthermore, we recently reported that serum- and glucocorticoid-regulated kinase 1 (SGK1) was an androgen-regulated gene in LNCaP cells and that it was required for androgenresponsive cell growth (Sherk et al., 2008).”
Self-citationChronic restraint stress attenuates p53 function and promotes tumorigenesis
Feng, Z., Liu, L., Zhang, C., Zheng, T., Wang, J., Lin, M., Zhao, Y., Wang, X., Levine, A. J., & Hu, W. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203930109 · Cited by 209
Birket, M. J., Ribeiro, M. C., Kosmidis, G., Ward, D., Leitoguinho, A. R., van de Pol, V., Dambrot, C., Devalla, H. D., Davis, R. P., Mastroberardino, P. G., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.09.025 · Cited by 203
Androgen-Induced Coactivator ANCCA Mediates Specific Androgen Receptor Signaling in Prostate Cancer
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The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex
Heikamp, E., Patel, C. H., Collins, S., Waickman, A. T., Oh, M. H., Sun, I., Illei, P. B., Sharma, A., Náray‐Fejes‐Tóth, A., Fejes‐Tóth, G., et al. (2014) · Nature Immunology · doi:10.1038/ni.2867 · Cited by 198
Mohammad, T., Siddiqui, S., Shamsi, A., Alajmi, M. F., Hussain, A., Islam, A., Ahmad, F., & Hassan, M. I. (2020) · Molecules · doi:10.3390/molecules25040823 · Cited by 162
“It has been found that GSK650394 can inhibit the androgen-stimulated growth of human prostate carcinoma LNCaP cells with an IC50 value of ~1 μM [10].”
BackgroundResultInfluentialSGK3 Mediates INPP4B-Dependent PI3K Signaling in Breast Cancer
Gasser, J. A., Inuzuka, H., Lau, A. W., Wei, W., Beroukhim, R., & Toker, A. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.09.023 · Cited by 148
“The arrow indicates the GSK-3b protein tment with GSK650394, SB415286, GSK650394 and SB415286, or MG132 in LAG-NDRG1, GST-Fbw7, HA-GSK-3b.”
BackgroundInfluentialFrigo, D. E., Howe, M. K., Wittmann, B. M., Brunner, A. M., Cushman, I., Wang, Q., Brown, M. A., Means, A. R., & McDonnell, D. P. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-2581 · Cited by 143
“In this regard, our group and others have shown that the targeting of specific signaling pathways downstream of AR represents a potential new modality for the treatment of prostate cancer (4-7).”
Self-citationPROTACs to address the challenges facing small molecule inhibitors
Martín-Acosta, P., & Xiao, X. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112993 · Cited by 192
The physiological impact of the serum and glucocorticoid-inducible kinase SGK1
Lang, F., Artunc, F., & Vallon, V. (2009) · Current Opinion in Nephrology and Hypertension · doi:10.1097/mnh.0b013e32832f125e · Cited by 139
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
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
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
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 102
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
“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].”
BackgroundSGK1 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
“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).”
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 120
Self-citationCao, Q., Wang, W., Williams, J. B., Yang, F., Wang, Z.-J., & Yan, Z. (2020) · Science Advances · doi:10.1126/sciadv.abc8096 · Cited by 108
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
“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.”
BackgroundResultInfluentialBago, 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 28
“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…”
Cristofano, A. D. (2016) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/bs.ctdb.2016.11.006 · Cited by 108
“The best-known and most used SGK1 inhibitor, GSK650394 (Sherk et al., 2008), has an IC50 of 64 nM for SGK1.”
InfluentialLang, F. J. W., Görlach, A., & Vallon, V. (2009) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728220903260807 · Cited by 106
“Along those lines, the SGK1 inhibitor GSK650394 has been proposed for anticancer therapy [110].”
BackgroundStimulation 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
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 96
“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…”
BackgroundMethodResultInfluentialOrai3 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 109
“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 89
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 93
“7 SGK1 inhibitors Two small molecule SGK1 inhibitors have been developed, GSK650394A [181] and EMD638683 [182].”
BackgroundInfluentialAndrogens 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 96
Self-citationGust, K. M., Hofer, M. D., Perner, S., Kim, R., Chinnaiyan, A. M., Varambally, S., Möller, P., Rinnab, L. J., Rubin, M. A., Greiner, J., et al. (2009) · Neoplasia · doi:10.1593/neo.09694 · Cited by 89
“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…”
BackgroundFrigo, 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
“Stealth siRNA (Invitrogen) transfections were previously described (30).”
BackgroundSelf-citationAmato, 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
“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].”
BackgroundDesign 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
HDAC6 selective inhibition of melanoma patient T-cells augments anti-tumor characteristics
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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 91
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 70
“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.”
BackgroundThe 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 85
“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].”
BackgroundOncogenic 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
Deng, W., Li, C., Tong, J., Zhang, W., & Wang, D. (2012) · Respiratory Research · doi:10.1186/1465-9921-13-29 · Cited by 71
“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…”
InfluentialSerum/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 77
“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].”
BackgroundSGK1 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 76
Gotoh, S., & Negishi, M. (2015) · Scientific Reports · doi:10.1038/srep14076 · Cited by 65
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
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
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
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
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
“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).”
BackgroundInfluentialPhosphorylation 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
“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.”
BackgroundChen, 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
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 57
“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.”
BackgroundSI113, 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
Scortegagna, M., Lau, E. K., Zhang, T., Feng, Y., Sereduk, C., Yin, H. H., De, S. K., Meeth, K. M., Platt, J. T., Langdon, C. G., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-14-2785 · Cited by 61
“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.”
MethodThe 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 59
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
“To determine the role of Sgk in mediating observed changes, a recently synthesized Sgk inhibitor (GSK650394A) was used [26].”
MethodPharmacological reactivation of inactive X-linked Mecp2 in cerebral cortical neurons of living mice
Przanowski, P., Wasko, U. N., Zheng, Z., Yu, J., Sherman, R., Zhu, L. J., McConnell, M. J., Tushir‐Singh, J., Green, M. R., & Bhatnagar, S. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803792115 · Cited by 55
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 59
“…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. M., Selman, P., Tonsing-Carter, E. Y., Bacalao, M. A., Lastra, R. 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 50
“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.”
BackgroundIncreased 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
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
“]; 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.”
BackgroundHall, B. A., Kim, T. Y., Skor, M. N., & Conzen, S. D. (2012) · Breast Cancer Research and Treatment · doi:10.1007/s10549-012-2161-y · Cited by 46
“the growth of both prostate and cervical cancer cells [25].”
BackgroundZhang, 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
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
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-citationAurora B Inhibitors as Cancer Therapeutics
Kovacs, A. H., Zhao, D.-J., & Hou, J.-Q. (2023) · Molecules · doi:10.3390/molecules28083385 · Cited by 39
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
“GSK650394 has been shown to delay cancer progression by inhibiting cell growth and inducing apoptosis in prostate cancer cells (49, 51, 52).”
BackgroundBradford, D., Raghuram, V., Wilson, J. L. L., Chou, C., Hoffert, J. D., Knepper, M. A., & Pisitkun, T. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00377.2012 · Cited by 47
“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…”
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 37
Li, X., Wang, Z., Jiao, C., Zhang, Y., Xia, N. L., Yu, W., Chen, X., Wikana, L. P., Liu, Y., Sun, L., et al. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-03977-z · Cited by 43
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
Mansley, M. K., & Wilson, S. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00898.x · Cited by 37
“…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).”
BackgroundMethodInfluentialSerum 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
“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…”
BackgroundInfluentialOrtuso, 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
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).”
BackgroundWang, Y.-Z., Zhou, D.-J., & Chen, S. (2014) · Molecular Endocrinology · doi:10.1210/me.2013-1339 · Cited by 35
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 45
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 35
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
“Next, we tested the impact of GSK650394, a selective SGK1 inhibitor [23,30], on ROS homeostasis.”
BackgroundMethodWang, 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
“GSK650394 is a pan-SGK inhibitor and blocks SGK1 activity in the nanomolar range, but inhibits SGK3 activity at higher concentrations (18).”
BackgroundSGK-1 protects kidney cells against apoptosis induced by ceramide and TNF-α
Pastore, D., Della‐Morte, D., Coppola, A., Capuani, B., Lombardo, M. F., 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 35
“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).”
MethodValidation of histone deacetylase 3 as a therapeutic target in castration‐resistant prostate cancer
McLeod, A., Stice, J. P., Wardell, S. E., Alley, H. M., Chang, C., & McDonnell, D. P. (2017) · The Prostate · doi:10.1002/pros.23467 · Cited by 33
Self-citationMatschke, J., Wiebeck, E., Hurst, S., Rudner, J., & Jendrossek, V. (2016) · Radiation Oncology · doi:10.1186/s13014-016-0647-1 · Cited by 31
“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].”
MethodRoles 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 37
Ossikbayeva, S., Khanin, M., Sharoni, Y., Trachtenberg, A., Tuleukhanov, S. T., Sensenig, R., Rom, S., Danilenko, M., & Orynbayeva, Z. (2021) · Antioxidants · doi:10.3390/antiox10101591 · Cited by 32
“In prostate cancer, SGK1 inhibition also has anti-androgen effects [97].”
BackgroundBertolin, A. P., Weissmann, F., Zeng, J., Posse, V., Milligan, J. C., Canal, B., Ulferts, R., Wu, M., Drury, L. S., Howell, M. T., et al. (2021) · Biochemical Journal · doi:10.1042/bcj20210200 · Cited by 36
“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).”
BackgroundO’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
Baban, B., Liu, J. Y., & Mozaffari, M. S. (2014) · American Journal of Hypertension · doi:10.1093/ajh/hpt269 · Cited by 29
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
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-citationLi, J., Zhou, Q., Yang, T., Li, Y., Zhang, Y., Wang, J., & Jiao, Z. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.02.002 · Cited by 30
Caohuy, H., Yang, Q., Eudy, Y., Ha, T.-A., Xu, A. E., Glover, M. L., Frizzell, R. A., Jozwik, C., & Pollard, H. B. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.598649 · Cited by 31
“9A also shows that when the incubation includes either PDK1 inhibitor GSK2334470 or SGK1 inhibitor GSK650394, Nedd4-2 is not phosphorylated.”
BackgroundMethodInfluentialEduful, 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
Self-citationAlamares-Sapuay, J. G., Martínez‐Gil, L., Stertz, S., Miller, M. S., Shaw, M. L., & Palese, P. (2013) · Journal of Virology · doi:10.1128/jvi.01258-12 · Cited by 21
“In the absence of androgens, GSK 650394 was not toxic to LNCaP cells (21).”
BackgroundNEDD4L 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
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
Maestro, I., Boya, P., & Martínez, A. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1730328 · Cited by 22
“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
Metadata
- 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)
- Venue
- Cancer Research
- Published
- 2008-09-14
- Volume
- 68
- Issue
- 18
- Pages
- 7475-7483
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › 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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