Identification of small-molecule inhibitors of the human S100B–p53 interaction and evaluation of their activity in human melanoma cells

Yoshimura, Chihoko; Miyafusa, Takamitsu; Tsumoto, Kouhei

doi:10.1016/j.bmc.2012.12.042

Cited by 19 publications

(15 citation statements)

References 30 publications

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“…Therefore, smallmolecule inhibitors targeting S100B-p53 interaction are under intense investigation as new therapeutic strategies for MM. 18,19 Overproduction of S100A4 as well as S100A6 has also been reported in MM. The upregulated expression of S100A4 is correlated with unfavorable prognosis in humans and higher metastatic potentials in murine xenograft models.…”

Section: Discussionmentioning

confidence: 94%

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Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma

Zhu

Ito

Nakahara

et al. 2013

The Journal of Dermatology

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S100P is a member of the S100 family. Increased levels of S100P have been documented in various malignancies. Binding of extracellular S100P to receptor for advanced glycation end products (RAGE) or coupling of intracellular S100P with a cytoskeletal protein, ezrin, play a crucial role in tumor growth, invasion and metastasis. However, little is known about the expression of S100P, RAGE and ezrin in malignant melanoma. We immunostained these three molecules in 20 primary and 20 metastatic melanomas. Samples of 20 benign nevus pigmentosus and 10 of normal skin were tested as controls. The expression levels (percentage of positively stained cells) of S100P, RAGE and ezrin were significantly higher in melanomas than in nevus pigmentosus. Moreover, slightly but significantly higher expression levels were observed in metastatic than in primary melanomas. Significant positive correlations were evident between the expression levels of S100P and RAGE, S100P and ezrin, and RAGE and ezrin, respectively. In conclusion, the coordinate upregulation of S100P, RAGE and ezrin may possibly facilitate malignant transformation of melanoma.

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Section: Discussionmentioning

confidence: 94%

“…Elevated S100B protein is known to downregulate p53 tumor suppressor protein, leading to cancer progression. Therefore, small‐molecule inhibitors targeting S100B–p53 interaction are under intense investigation as new therapeutic strategies for MM . Overproduction of S100A4 as well as S100A6 has also been reported in MM.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma

Zhu

Ito

Nakahara

et al. 2013

The Journal of Dermatology

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“…These approaches have successfully identified new compounds that inhibit the interactions of S100P 149 , S100A4 (REFS 156,157), S100A9 (REF. 156), S100A10 (REF 158) and S100B 123,159 with their respective targets. An examination of these S100–small-molecule complexes has revealed that most small molecules target one of three distinct pockets within S100 proteins 160 (FIG.…”

Section: Targeting S100 Proteinsmentioning

confidence: 99%

S100 proteins in cancer

2015

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In humans, the S100 protein family is composed of 21 members that exhibit a high degree of structural similarity, but are not functionally interchangeable. This family of proteins modulates cellular responses by functioning both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated expression of multiple members of the S100 family is a common feature of human cancers, with each type of cancer showing a unique S100 protein profile or signature. Emerging in vivo evidence indicates that the biology of most S100 proteins is complex and multifactorial, and that these proteins actively contribute to tumorigenic processes such as cell proliferation, metastasis, angiogenesis and immune evasion. Drug discovery efforts have identified leads for inhibiting several S100 family members, and two of the identified inhibitors have progressed to clinical trials in patients with cancer. This Review highlights new findings regarding the role of S100 family members in cancer diagnosis and treatment, the contribution of S100 signalling to tumour biology, and the discovery and development of S100 inhibitors for treating cancer.

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“…This model should help direct further structural studies to resolve the stoichiometry and dynamics of the interaction of S100B with other proposed target proteins. It may also facilitate the design of new chemical inhibitors for therapeutic purposes (Yoshimura, Miyafusa & Tsumoto, ; Cavalier et al ., ,b; Bresnick, ). Finally, a chaperone‐associated function for intracellular S100B is discussed.…”

Section: Introductionmentioning

confidence: 99%

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

2020

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The S100 genes encode a conserved group of 21 vertebrate-specific EF-hand calcium-binding proteins. Since their discovery in 1965, S100 proteins have remained enigmatic in terms of their cellular functions. In this review, we summarize the calcium-and zinc-binding properties of the dimeric S100B and S100A1 proteins and highlight data that shed new light on the extracellular and intracellular regulation and functions of S100B. We point out that S100B and S100A1 homodimers are not functionally interchangeable and that in a S100A1/S100B heterodimer, S100A1 acts as a negative regulator for the ability of S100B to bind Zn 2+ . The Ca 2+ and Zn 2+ -dependent interactions of S100B with a wide array of proteins form the basis of its activities and have led to the derivation of some initial rules for S100B recognition of protein targets. However, recent findings have strongly suggested that these rules need to be revisited. Here, we describe a new consensus S100B binding motif present in intracellular and extracellular vertebrate-specific proteins and propose a new model for stable interactions of S100B dimers with full-length target proteins. A chaperone-associated function for intracellular S100B in adaptive cellular stress responses is also discussed. This review may help guide future studies on the functions of S100 proteins in general.Biological Reviews 95 (2020) 738-758

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Identification of small-molecule inhibitors of the human S100B–p53 interaction and evaluation of their activity in human melanoma cells

Cited by 19 publications

References 30 publications

Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma

Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma

S100 proteins in cancer

The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths

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Identification of small-molecule inhibitors of the human S100B–p53 interaction and evaluation of their activity in human melanoma cells

Cited by 19 publications

References 30 publications

Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma

Upregulation of S100P, receptor for advanced glycation end products and ezrin in malignant melanoma

S100 proteins in cancer

The Zn2+ and Ca2+‐binding S100B and S100A1 proteins: beyond the myths

Contact Info

Product

Resources

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The Zn²⁺ and Ca²⁺‐binding S100B and S100A1 proteins: beyond the myths