Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors

Hammond, Marlys; Washburn, David G.; Hoang, Tram H.; Manns, Sharada; Frazee, James S.; Nakamura, Hiroko; Patterson, Jaclyn R.; Trizna, Walter; Wu, Chunchi; Azzarano, Leonard M.; Nagilla, Rakesh; Nord, Melanie; Trejo, Rebecca; Head, Martha S.; Zhao, Baoguang; Smallwood, Angela; Hightower, Kendra E.; Laping, Nicholas J.; Schnackenberg, Christine G.; Thompson, Scott K.

doi:10.1016/j.bmcl.2009.05.051

Cited by 41 publications

(29 citation statements)

References 6 publications

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“…SGK1 is of particular interest as an AR/GR target gene in CRPC as it is activated by phosphorylation downstream of PI3-K/mTOR signaling, which is often aberrantly activated in PC especially in the setting of complete AR blockade [6]. Therefore, SGK1 inhibition may be a viable treatment strategy along with inhibiting AR activity (e.g., abiraterone or enzalutamide) [17]. …”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Activity Contributes to Resistance to Androgen-Targeted Therapy in Prostate Cancer

et al. 2014

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Despite new treatments for castrate-resistant prostate cancer (CRPC), the prognosis of patients with CRPC remains bleak due to acquired resistance to androgen receptor (AR)-directed therapy. The glucocorticoid receptor (GR) and AR share several transcriptional targets, including the anti-apoptotic genes serum and glucocorticoid-regulated kinase 1 (SGK1) and Map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Because GR expression increases in a subset of primary prostate cancer (PC) following androgen deprivation therapy, we sought to determine whether GR activation can contribute to resistance to AR-directed therapy. We studied CWR-22Rv1 and LAPC4 AR/GR-expressing PC cell lines following treatment with combinations of the androgen R1881, AR antagonist MDV3100, GR agonist dexamethasone, GR antagonists mifepristone and CORT 122928, or the SGK1 inhibitor GSK650394. Cell lines stably expressing GR (NR3C1)-targeted shRNA or ectopic SGK1-Flag were also studied in vivo. GR activation diminished the effects of the AR antagonist MDV3100 on tumor cell viability. In addition, GR activation increased prostate-specific antigen (PSA) secretion and induced SGKI and MKP1/DUSP gene expression. Glucocorticoid-mediated cell viability was diminished by a GR antagonist or by co-treatment with the SGK1 inhibitor GSK650394. In vivo, GR depletion delayed castrate-resistant tumor formation, while SGK1-Flag-overexpressing PC xenografts displayed accelerated castrate-resistant tumor initiation, supporting a role for SGK1 in GR-mediated CRPC progression. We studied several PC models before and following treatment with androgen blockade and found that increased GR expression and activity contributed to tumor-promoting PC cell viability. Increased GR-regulated SGK1 expression appears, at least in part, to mediate enhanced PC cell survival. Therefore, GR and/or SGK1 inhibition may be useful adjuncts to AR blockade for treating CRPC.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid Receptor Activity Contributes to Resistance to Androgen-Targeted Therapy in Prostate Cancer

et al. 2014

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“…Indoles substituted at C-3 [71,72] and their aza analogues [73] are known to exhibit remarkable biological activities. Particularly in the case of azaindoles, their ability to bind to the hinge region of kinases renders them promising structural motifs for kinase inhibition studies [74][75][76][77]. Thus a one-pot multicomponent strategy was developed involving the coupling of N-Boc protected 3-iodo NH-heterocycles with (trimethylsilyl)acetylene that furnished the TMS-protected heterocyclic alkynes as intermediates, which, after in situ deprotection, gave rise to terminal alkynes that underwent subsequent CuAAC with an azide to furnish 3-triazolyl indoles or aza-indoles 15 (Scheme 8) [78].…”

Section: Methodsmentioning

confidence: 99%

Sequentially Palladium-Catalyzed Processes in One-Pot Syntheses of Heterocycles

Lessing

Müller

2015

Applied Sciences

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Sequentially Pd-catalyzed processes are excellent entries to heterocycle synthesis. The broad mechanistic variety combined with often very mild reaction conditions allow the concatenation of elementary organic and organometallic steps to novel sequences in the sense of one-pot domino and multicomponent reactions. Given the numerous opportunities of alkyne coordination and their Pd-mediated transformations, alkynylation and carbometallation play a key role, both for purely organometallic sequences as well as in those processes that are intercepted by cyclocondensation. Pd-catalyzed aminations also find more and more entry into novel heterocycle syntheses based upon this theme.

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“…S1A). We treated bone marrow mononuclear cells (BMM) once a day with different concentrations of GSK650394, an SGK1 inhibitor, in the presence of RANKL (100 ng/mL) and M-CSF (30 ng/mL) for 7 days (29). Osteoclast formation were inhibited in a dose-dependent manner ( Fig.…”

Section: Suppression Of Sgk1 Inhibits Rankl-induced Osteoclastogenesimentioning

confidence: 99%

Serum- and Glucocorticoid-inducible Kinase 1 is Essential for Osteoclastogenesis and Promotes Breast Cancer Bone Metastasis

Zheng

Song

et al. 2020

Molecular Cancer Therapeutics

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◥Bone metastasis is a severe complication associated with various carcinomas. It causes debilitating pain and pathologic fractures and dramatically impairs patients' quality of life. Drugs aimed at osteoclast formation significantly reduce the incidence of skeletal complications and are currently the standard treatment for patients with bone metastases. Here, we reported that serum-and glucocorticoid-inducible kinase 1 (SGK1) plays a pivotal role in the formation and function of osteoclasts by regulating the Ca 2þ release-activated Ca 2þ channel Orai1. We showed that SGK1 inhibition represses osteoclastogenesis in vitro and prevents bone loss in vivo. Furthermore, we validated the effect of SGK1 on bone metastasis by using an intracardiac injection model in mice. Inhibition of SGK1 resulted in a significant reduction in bone metastasis. Subsequently, the Oncomine and the OncoLnc database were employed to verify the differential expression and the association with clinical outcome of SGK1 gene in patients with breast cancer. Our data mechanistically demonstrated the regulation of the SGK1 in the process of osteoclastogenesis and revealed SGK1 as a valuable target for curing bone metastasis diseases. Materials and Methods ReagentsGSK650394 and BTP2 was purchased from Sigma-Aldrich. Soluble recombinant human M-CSF and mouse RANKL were obtained from PeproTech.

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Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors

Cited by 41 publications

References 6 publications

Glucocorticoid Receptor Activity Contributes to Resistance to Androgen-Targeted Therapy in Prostate Cancer

Glucocorticoid Receptor Activity Contributes to Resistance to Androgen-Targeted Therapy in Prostate Cancer

Sequentially Palladium-Catalyzed Processes in One-Pot Syntheses of Heterocycles

Serum- and Glucocorticoid-inducible Kinase 1 is Essential for Osteoclastogenesis and Promotes Breast Cancer Bone Metastasis

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