Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis

Fen, Jiang; Guo, An-ping; Xu, Jiachen; You, Qidong; Xu, Xiu

doi:10.1021/acs.jmedchem.8b00800

Cited by 34 publications

(30 citation statements)

References 51 publications

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“…GRPs are stress-responsive proteins located mainly in the mitochondria and ER. Different GRPs directed therapeutic compounds are being developed [33,34]. Our previous study found that GRP94-KD played a role in chemoresistance of squamous cells of cervical cancer and esophageal cancer [19,28].…”

Section: Discussionmentioning

confidence: 99%

Glucose-Regulated Protein 94 Mediates the Proliferation and Metastasis through the Regulation of ETV1 and MAPK Pathway in Colorectal Cancer

Batzorig¹,

Wei²,

Wang³

et al. 2021

Int. J. Med. Sci.

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Colorectal cancer (CRC) is a worldwide health problem. Glucose-regulated protein 94 (GRP94) is known as an important endoplasmic reticulum-stress response protein that shows correlation with aggressive cancer behavior. However, the role of GRP94 in CRC is still unclear. Our results showed that silencing GRP94 (GRP94-KD) reduced cell proliferation, invasion and migration of CRC cells and suppressed tumorigenesis in the xenograft mouse model. Rescue assay showed that ETV1 overexpression reversed the effect of GRP94 on cell proliferation and migration. In the molecular mechanism, we found that knockdown of GRP94 inhibited the level of MAPK pathway, including ERK/p-ERK, JNK/p-JNK, and p38/p-p38 signals. Cyclooxygenase-2 and epithelial-mesenchymal transformation biomarkers, such as N-cadherin, vimentin, and β-catenin were suppressed in GRP94 knockdown cells. Treatment of specific inhibitors of MAPK pathway showed that ERK/p-ERK, and p38/p-p38 inhibitors significantly influenced ETV1 expression as compared to JNK/p-JNK inhibitor. Our results indicated that silencing GRP94 repressed the ability of EMT process, cancer cell proliferation, metastasis, and CRC tumorigenesis. Therefore, GRP94 may play an important role in CRC by regulating ETV1 and MAPK pathway.

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Section: Discussionmentioning

confidence: 99%

Glucose-Regulated Protein 94 Mediates the Proliferation and Metastasis through the Regulation of ETV1 and MAPK Pathway in Colorectal Cancer

Batzorig¹,

Wei²,

Wang³

et al. 2021

Int. J. Med. Sci.

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“…10d, e, nebivolol treatment or ectopic expression of FBXL2 reduced EGFR T790M/C797S protein expression, concomitant with suppression of cell proliferation. In addition, nebivolol-induced suppression of cell proliferation was markedly enhanced by Grp94-specific inhibitor (Grp94 inhibitor-1, iGrp94-1 41 ) (Supplementary Fig. 10f).…”

Section: Fbxl2 Inhibits Nsclc Growth Via Downregulation Of Egfr Expressionmentioning

confidence: 99%

FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth

Niu

Liu

et al. 2021

Nat Commun

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Abnormal activation of epidermal growth factor receptor (EGFR) drives non-small cell lung cancer (NSCLC) development. EGFR mutations-mediated resistance to tyrosine-kinase inhibitors (TKIs) is a major hurdle for NSCLC treatment. Here, we show that F-box protein FBXL2 targets EGFR and EGFR TKI-resistant mutants for proteasome-mediated degradation, resulting in suppression of EGFR-driven NSCLC growth. Reduced FBXL2 expression is associated with poor clinical outcomes of NSCLC patients. Furthermore, we show that glucose-regulated protein 94 (Grp94) protects EGFR from degradation via blockage of FBXL2 binding to EGFR. Moreover, we have identified nebivolol, a clinically used small molecule inhibitor, that can upregulate FBXL2 expression to inhibit EGFR-driven NSCLC growth. Nebivolol in combination with osimertinib or Grp94-inhibitor-1 exhibits strong inhibitory effects on osimertinib-resistant NSCLC. Together, this study demonstrates that the FBXL2-Grp94-EGFR axis plays a critical role in NSCLC development and suggests that targeting FBXL2-Grp94 to destabilize EGFR may represent a putative therapeutic strategy for TKI-resistant NSCLC.

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“…Recently, the Xu group developed a GRP94 selective inhibitor, Compound 54, with an IC50 of 2 nM and over 1,000fold selectivity for GRP94 versus HSP90a. They found that this compound has anti-inflammation efficacy in the DSS-induced colitis mouse model (113). However, Compound 54 hasn't been tested in the treatment of cancers.…”

Section: Small Molecular Inhibitorsmentioning

confidence: 99%

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target

et al. 2021

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During tumor development and progression, intrinsic and extrinsic factors trigger endoplasmic reticulum (ER) stress and the unfolded protein response, resulting in the increased expression of molecular chaperones to cope with the stress and maintain tumor cell survival. Heat shock protein (HSP) GRP94, also known as GP96, is an ER paralog of HSP90 and has been shown to promote survival signaling during tumor-induced stress and modulate the immune response through its multiple clients, including TLRs, integrins, LRP6, GARP, IGF, and HER2. Clinically, elevated expression of GRP94 correlates with an aggressive phenotype and poor clinical outcome in a variety of cancers. Thus, GRP94 is a potential molecular marker and therapeutic target in malignancies. In this review, we will undergo deep molecular profiling of GRP94 in tumor development and summarize the individual roles of GRP94 in common cancers, including breast cancer, colon cancer, lung cancer, liver cancer, multiple myeloma, and others. Finally, we will briefly review the therapeutic potential of selectively targeting GRP94 for the treatment of cancers.

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Discovery of a Potent Grp94 Selective Inhibitor with Anti-Inflammatory Efficacy in a Mouse Model of Ulcerative Colitis

Cited by 34 publications

References 51 publications

Glucose-Regulated Protein 94 Mediates the Proliferation and Metastasis through the Regulation of ETV1 and MAPK Pathway in Colorectal Cancer

Glucose-Regulated Protein 94 Mediates the Proliferation and Metastasis through the Regulation of ETV1 and MAPK Pathway in Colorectal Cancer

FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth

Molecular Chaperone GRP94/GP96 in Cancers: Oncogenesis and Therapeutic Target

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