Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer

Guo, Zhongqiang; Zheng, Tong; Chen, Baoen; Luo, Cheng; Ouyang, Sisheng; Gong, Shouzhe; Li, Jiafei; Mao, Liu‐Liang; Lian, Fulin; Yang, Yong; Huang, Yue; Li, Li; Lü, Jing; Zhang, Bidong; Zhou, Luming; Ding, Hong; Gao, Zhiwei; Zhou, Liqun; Li, Guoqiang; Zhou, Ran; Chen, Ke; Liu, Ying; Wen, Yi; Gong, Likun; Ke, Youqi; Yang, Shang‐Dong; Qiu, Xiao‐Bo; Zhang, Naixia; Ren, Jin; Zhong, Dafang; Yang, Cai‐Guang; Liu, Jiang; Jiang, Hualiang

doi:10.1016/j.ccell.2016.08.003

Cited by 72 publications

(97 citation statements)

References 35 publications

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“…Furthermore, we observed a dose-dependent attenuation of signal in the Carr-Purcell-Meiboom-Gill nuclear magnetic resonance (NMR) spectra, confirming that DHODH influences the state of isobavachalcone (Figure 2E). 27 In addition, isobavachalcone bound to DHODH with a K D value of 1.33 μM (Figure 2F), according to an isothermal titration calorimetry experiment, which is consistent with results of the thermal shift assay and NMR experiments.…”

Section: Resultssupporting

confidence: 83%

Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells

Wang

Chen

et al. 2018

Haematologica

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Acute myeloid leukemia is a disorder characterized by abnormal differentiation of myeloid cells and a clonal proliferation derived from primitive hematopoietic stem cells. Interventions that overcome myeloid differentiation have been shown to be a promising therapeutic strategy for acute myeloid leukemia. In this study, we demonstrate that CRISPR/Cas9-mediated knockout of dihydroorotate dehydrogenase leads to apoptosis and normal differentiation of acute myeloid leukemia cells, indicating that dihydroorotate dehydrogenase is a potential differentiation regulator and a therapeutic target in acute myeloid leukemia. By screening a library of natural products, we identified a novel dihydroorotate dehydrogenase inhibitor, isobavachalcone, derived from the traditional Chinese medicine Psoralea corylifolia. Using enzymatic analysis, thermal shift assay, pull down, nuclear magnetic resonance, and isothermal titration calorimetry experiments, we demonstrate that isobavachalcone inhibits human dihydroorotate dehydrogenase directly, and triggers apoptosis and differentiation of acute myeloid leukemia cells. Oral administration of isobavachalcone suppresses subcutaneous HL60 xenograft tumor growth without obvious toxicity. Importantly, our results suggest that a combination of isobavachalcone and adriamycin prolonged survival in an intravenous HL60 leukemia model. In summary, this study demonstrates that isobavachalcone triggers apoptosis and differentiation of acute myeloid leukemia cells via pharmacological inhibition of human dihydroorotate dehydrogenase, offering a potential therapeutic strategy for acute myeloid leukemia.

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Section: Resultssupporting

confidence: 83%

Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells

Wang

Chen

et al. 2018

Haematologica

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“…SPOP is over-expressed in almost 100% of ccRCC samples 170 , where it is confined to the cytoplasm, in contrast to non-RCC cancers 13,171 . Cytoplasmic CRL3–SPOP drives the degradation of several negative regulators of proliferation (for example, PTEN, dual specificity protein phosphatase 7 (DUSP7) and the transcription factor GLI2) and apoptosis (for example, death domain-associated protein 6 (DAXX)) 13 .…”

Section: Cell Death Regulation By Ubiquitin Ligasesmentioning

confidence: 97%

“…Consequently, knockdown of SPOP inhibits proliferation and induces apoptosis of ccRCC cells but not of non-RCC cells, such as the cervical cancer cell line HeLa or the HEK293 cell line 13 . Small-molecule inhibitors of CRL3–SPOP–substrate interactions demonstrate selective killing of human ccRCC cells but not of cells lacking cytoplasmic accumulation of SPOP 171 . Thus, the cytoplasmic localization of SPOP seems to shift its function from a pro-apoptotic (in the nucleus) to an anti-apoptotic and pro-proliferative E3.…”

Section: Cell Death Regulation By Ubiquitin Ligasesmentioning

confidence: 98%

“…Structure-based design, combined with advanced small-molecule screening technologies, is among the current approaches used for the development of E3 inhibitors. Pursuing these approaches has led to the development of E3 inhibitors that are currently being evaluated in the clinical and preclinical setting, including inhibitors of APC/C 20,21 , MDM2 (REFS 57,58), SKP2 (REFS 88,184), SPOP 171 and cIAP 182,185 . However, it is not trivial to develop modulators of protein–protein interactions, and inhibition of E3s is currently one of the more challenging areas of drug development.…”

Section: Ubiquitin Ligases As Therapeutic Targetsmentioning

confidence: 99%

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Ubiquitin ligases in oncogenic transformation and cancer therapy

2017

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The cellular response to external stress signals and DNA damage depends on the activity of ubiquitin ligases (E3s), which regulate numerous cellular processes, including homeostasis, metabolism and cell cycle progression. E3s recognize, interact with and ubiquitylate protein substrates in a temporally and spatially regulated manner. The topology of the ubiquitin chains dictates the fate of the substrates, marking them for recognition and degradation by the proteasome or altering their subcellular localization or assembly into functional complexes. Both genetic and epigenetic alterations account for the deregulation of E3s in cancer. Consequently, the stability and/or activity of E3 substrates are also altered, in some cases leading to downregulation of tumour-suppressor activities and upregulation of oncogenic activities. A better understanding of the mechanisms underlying E3 regulation and function in tumorigenesis is expected to identify novel prognostic markers and to enable the development of the next generation of anticancer therapies. This Review summarizes the oncogenic and tumour-suppressor roles of selected E3s and highlights novel opportunities for therapeutic intervention.

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“…Additionally, researchers have found that compound 6b have no interf- erence on the other type of ring finger ligase RNF5. Proof thus far verifies that the compound 6b showing anti-ccRCC effect is on its target (Guo et al, 2016). Overall, this is interesting and potentially important research describing small molecules that bind directly to the SPOP subunit of the SPOP E3 ubiquitin ligase complex and inhibit the growth of renal carcinoma cells in vitro and in vivo.…”

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Targeting SPOP with small molecules provides a novel strategy for kidney cancer therapy

Zheng

Yang

2016

Sci. China Life Sci.

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Renal cell carcinoma (RCC), accounting for 4% of all cancers, is the second most common cancer in urology. The most common form of RCC is clear cell RCC (ccRCC), with a ratio over 70%. Early-phase kidney diseases usually show rare symptoms in clinic; unfortunately, most patients are diagnosed with kidney cancer at the end stage, at which point the cancer is both resistant to chemotherapy and metastatic, thus leading to high mortality. Understanding cancer biology enables manipulation of disease targets by using small-molecule modulators, which eventually drive the development of novel therapeutic agents for ccRCC. In this insight, we would like to briefly outline several promising and revolutionizing targets and the target-based design of therapeutic agents for ccRCC.Interleukin-2 (Aldesleukin) and interferon are common immunotherapy for patients with metastatic RCC, while their effectiveness is still controversial. In 2015, the first checkpoint inhibitor nivolumab (Opdivo, BMS) with improved overall survival for the RCC therapy was approved by the FDA (Food and Drug Administration) as a single agent in the second-line setting, which is a monoclonal antibody targeting PD-1 in order to suppress the growth of ccRCC cells. Comparing checkpoint-inhibitor based combinations with other anti-tumor agents in the first-line setting are ongoing in phase III for *Corresponding author (email: yangcg@simm.ac.cn) ccRCC therapy. With several checkpoint inhibitors alone or in combination, this field is promising and evolving rapidly (Curtis et al., 2016).Hereditary or sporadic ccRCC always demonstrates correlation with the inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), lowing ubiquitination level of the down-stream protein hypoxic stress and hypoxia-inducible factor α (HIFα), and bringing about its stabilization and accumulation in ccRCC cells. Cellular stimuli activate the phosphoinositide 3-kinase (PI3K)/Akt (protein kinase) pathway and mammalian target of rapamycin (mTOR), which can also raise the HIFα protein level in ccRCC cells. Consequently, the activated transcription factor HIF increases the transcription level of hypoxia-related genes, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), and results in tumor-inclined cell proliferation, migration, and permeation. There is considerable pharmaceutical research into drug discovery by targeting protein phosphorylation signaling pathways. Indeed, the FDA has approved several agents targeting ccRCC-closely related proteins for the metastatic RCC therapy. Temsirolimus (Torisel, Wyeth), an inhibitor of mTOR conplex1 (mTORC1), shows good antitumor activity in patients with metastatic RCC. VEGF receptor (VEGFR) and PDGF receptor (PDGRF) tyrosine kinases inhibitors sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer) are released to the market for the treatment of RCC.

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Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer

Cited by 72 publications

References 35 publications

Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells

Pharmacological inhibition of dihydroorotate dehydrogenase induces apoptosis and differentiation in acute myeloid leukemia cells

Ubiquitin ligases in oncogenic transformation and cancer therapy

Targeting SPOP with small molecules provides a novel strategy for kidney cancer therapy

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