Chemical probes of Skp2-mediated p27 ubiquitylation and degradation

Lough, Lea; Sherman, Dan; Ni, Eric; Young, Lauren M.; Hao, Bing; Cardozo, Timothy

doi:10.1039/c8md00140e

Cited by 16 publications

(12 citation statements)

References 42 publications

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“…Thus, inactivation of SCF SKP2 complexes provides a concept of using synthetic lethality as a therapeutic strategy against retinoblastoma. However, no chemically synthesized probes have been qualified as validated pharmaceutical hit compounds to suppress SKP2 activity [ 159 ].…”

Section: Treatmentsmentioning

confidence: 99%

Retinoblastoma: Etiology, Modeling, and Treatment

Kaewkhaw

Rojanaporn

2020

Cancers

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Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. These are important to establish reliable preclinical models to study the disease and develop therapies. Although retinoblastoma is the most curable pediatric cancer with a high survival rate, advanced tumors limit globe salvage and are often associated with high-risk histopathological features predictive of dissemination. The advent of chemotherapy has improved treatment outcomes, which is effective for globe preservation with new routes of targeted drug delivery. However, molecularly targeted therapeutics with more effectiveness and less toxicity are needed. Here, we review the current knowledge concerning retinoblastoma genesis with particular attention to the genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, as well as the retinoblastoma cell-of-origin and current disease models. We further discuss current treatments, clinicopathological correlations, which assist in guiding treatment and may facilitate globe preservation, and finally we discuss targeted therapeutics for future treatments.

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Section: Treatmentsmentioning

confidence: 99%

Retinoblastoma: Etiology, Modeling, and Treatment

Kaewkhaw

Rojanaporn

2020

Cancers

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“…Skp2‐targeted therapy has emerged as an efficient approach to inhibit the proliferation, metastasis, and stemness of cancer. Multiple chemical probes have been demonstrated to target Skp2 and inhibit Skp2‐mediated degradation of p27 11,33,34 . In the present study, we further explored novel Skp2 inhibitors that may qualify as anticancer drug candidates.…”

Section: Discussionmentioning

confidence: 96%

“…Multiple chemical probes have been demonstrated to target Skp2 and inhibit Skp2‐mediated degradation of p27. 11 , 33 , 34 In the present study, we further explored novel Skp2 inhibitors that may qualify as anticancer drug candidates. Based on high‐throughput virtual screening, we identified BA as a potent Skp2 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Phytochemical library screening reveals betulinic acid as a novel Skp2‐SCF E3 ligase inhibitor in non–small cell lung cancer

Chen

Zhou

et al. 2021

Cancer Science

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Skp2 is overexpressed in multiple cancers and plays a critical role in tumor development through ubiquitin/proteasome‐dependent degradation of its substrate proteins. Drugs targeting Skp2 have exhibited promising anticancer activity. Here, we identified a plant‐derived Skp2 inhibitor, betulinic acid (BA), via high‐throughput structure‐based virtual screening of a phytochemical library. BA significantly inhibited the proliferation and migration of non–small cell lung cancer (NSCLC) through targeting Skp2‐SCF E3 ligase both in vitro and in vivo. Mechanistically, BA binding to Skp2, especially forming H‐bonds with residue Lys145, decreases its stability by disrupting Skp1‐Skp2 interactions, thereby inhibiting the Skp2‐SCF E3 ligase and promoting the accumulation of its substrates; that is, E‐cadherin and p27. In both subcutaneous and orthotopic xenografts, BA significantly inhibited the proliferation and metastasis of NSCLC through targeting Skp2‐SCF E3 ligase and upregulating p27 and E‐cadherin protein levels. Taken together, BA can be considered a valuable therapeutic candidate to inhibit metastasis of NSCLC.

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“…In particular, deletion of SKP2 resulted in accumulation of p27 Kip1 and p57 Kip2 CDKIs (Lough et al, 2018). Destruction of p27 Kip1 and p57 Kip2 through ubiquitin-mediated proteolysis via SKP2 reveals that SKP2 regulates HSC quiescence, maintenance and self-renewal.…”

Section: Introductionmentioning

confidence: 98%

Small molecule‐mediated modulation of ubiquitination and neddylation improves HSC function ex vivo

Albayrak

Uslu

Akgöl

et al. 2021

Journal Cellular Physiology

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Hematopoietic stem cells (HSCs) are particularly characterized by their quiescence and self-renewal. Cell cycle regulators tightly control quiescence and self-renewal capacity. Studies suggest that modulation of ubiquitination and neddylation could contribute to HSC function via cyclin-dependent kinase inhibitors (CDKIs). S-phase kinase-associated protein 2 (SKP2) is responsible for ubiquitin-mediated proteolysis of CDKIs. Here, we modulated overall neddylation and SKP2-associated ubiquitination in HSCs by using SKP2-C25, an SKP2 inhibitor, and MLN4924 (Pevonedistat) as an inhibitor of the NEDD8 system. Treatments of SKP2-C25 and MLN4924 increased both murine and human stem and progenitor cell (HSPC) compartments. This is associated with the improved quiescence of murine HSC by upregulation of p27 and p57 CDKIs. A colony-forming unit assay showed an enhanced in vitro selfrenewal potential post inhibition of ubiquitination and neddylation. In addition, MLN4924 triggered the mobilization of bone marrow HSPCs to peripheral blood.Intriguingly, MLN4924 treatment could decrease the proliferation of murine bone marrow mesenchymal stem cells or endothelial cells. These findings shed light on the contribution of SKP2, and associated ubiquitination and neddylation in HSC maintenance, self-renewal, and expansion.

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Chemical probes of Skp2-mediated p27 ubiquitylation and degradation

Cited by 16 publications

References 42 publications

Retinoblastoma: Etiology, Modeling, and Treatment

Retinoblastoma: Etiology, Modeling, and Treatment

Phytochemical library screening reveals betulinic acid as a novel Skp2‐SCF E3 ligase inhibitor in non–small cell lung cancer

Small molecule‐mediated modulation of ubiquitination and neddylation improves HSC function ex vivo

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