Elsevier

Drug Discovery Today

Volume 25, Issue 9, September 2020, Pages 1754-1761
Drug Discovery Today

Review
Post screen
Interfering with S100B–effector protein interactions for cancer therapy

https://doi.org/10.1016/j.drudis.2020.07.010Get rights and content

Highlights

  • S100B is overexpressed in various malignant tumors.

  • S100B exerts its biofunctions by physical interactions with other molecules.

  • Interfering with S100B-effector protein interactions is a potential strategy for cancer therapy.

  • Virtual screening is an efficient approach to identify protein–protein interactions inhibitor.

S100 calcium-binding protein B (S100B) is overexpressed in various malignant tumors, where it regulates cancer cell proliferation and metabolism by physical interactions with other molecules. Interfering with S100B–effector protein interactions is a potential strategy to treat malignant tumors. Although some S100B inhibitors have been discovered by virtual screening (VS), most target the S100B–p53 interaction. Hence, there is scope for the discovery of other S100B–effector protein interaction modulators for malignant tumors. In this review, we provide an overview of S100B–effector protein interaction inhibitor discovery using VS and discuss promising S100B–effector protein interaction targets that permit in silico analysis for drug discovery.

Introduction

S100B is a homodimeric Ca2+-binding protein that is involved in the regulation of intracellular and extracellular processes 1, 2. Structurally, S100B contains four helices in each subunit. The canonical 10–12-residue EF-hand comprises helix 3, helix 4, and loop 2, whereas the 14-residue N-terminal pseudo-EF-hand comprises helix 1, helix 2, and loop 1. When S100B binds to Ca2+, helix 3 undergoes a significant conformational change to become perpendicular to helix 4, revealing a hydrophobic pocket for interaction with its targets 3, 4, 5. Unlike other proteins, S100B is not a ubiquitous protein, and its expression is restricted to astrocytes and melanocytes [6]. As an intracellular regulator, S100B mainly localizes in the cytoplasm and regulates cell proliferation, Ca2+ homeostasis, protein phosphorylation, enzyme activity, and metabolism via physical interactions with its target molecules, including the tumor suppressor p53, CapZ, the RAGE receptor, Hdm2, NDR kinase protein kinase Cα, the dopamine D2 receptor, and ribosomal S6 kinase 1 (RSK1) [7]. When S100B is actively released by astrocytes and adipocytes, it acts as an extracellular signal [8].

At low physiological levels, S100B protects neurons against apoptosis and stimulates astrocyte proliferation via upregulating the antiapoptotic factor, Bcl-2, via engagement of RAGE and activation of the MAPK pathway [8], whereas, at high levels, S100B causes neuronal death via the Akt/p21 pathway 6, 8. Moreover, accumulating evidence reveals that S100B is overexpressed in various malignant tumors and that S100B–effector proteins interactions are important for tumor growth. For example, S100B can interact with p53 to inhibit p53 function, whereas disrupting S100B–p53 interference can suppress tumor growth 9, 10. The high binding affinity of the S100B and RAGE interaction was observed in glioma cells, whereas blocking the S100B–RAGE interaction suppressed STAT3 pathway to reduce glioma growth in vivo [10]. In addition, S100B directly binds to RSK as well as retaining RSK in the cytoplasm, and promotes aberrant ERK/RSK activity to induce cancer cell proliferation [11]. Although S100B–effector protein interactions are not fully understood, research demonstrates the modulation of the S100B–effector protein interaction as a promising strategy for S100B-dependent tumor therapy.

Computer-aided approaches, including VS, have been utilized to assist the development of protein–protein interaction (PPI) inhibitors [12]. Although some S100B inhibitors have been reported using VS, most target the S100B–p53 interaction for melanoma therapy [10]. In this review, we provide an overview of S100B–effector protein interaction inhibitor discovery using VS. We discuss promising S100B–effector protein interaction targets, especially those with characterized 3D structures that enable in silico analysis for S100B-dependent cancer therapy drug discovery.

Section snippets

Role of S100B in tumorigenesis

Overexpressed S100B is observed in various highly malignant cancers and can physically interacts with its target effector proteins to regulate tumor growth (Fig. 1) 8, 13, 14. Here, we discuss the role of S100B in the tumorigenesis of various human cancers.

Application of VS for S100B–effector protein interaction inhibitor discovery

Computer-aided drug design (CADD), including VS, has emerged as an efficient approach to identify small-molecule PPI modulators [12]. VS methods can be traditionally divided into two broad types: structure-based VS (SBVS) and ligand-based VS (LBVS). In general, SBVS depends on the knowledge of the target protein 3D structure to screen target molecules, whereas LBVS is based on knowledge of known active and inactive molecules from a ligand database [40]. Integrating SBVS and LBVS approaches can

Targeting S100B–effector protein interactions for cancer therapy

As described earlier, S100B dysfunction induces cancer cell proliferation and metastasis via regulating protein phosphorylation, transcription, enzyme activity, and metabolism 60, 61, 62. Therefore, interfering with S100B–effector protein interactions is an emerging strategy for S100B-dependent cancer therapy 3, 15, 16. However, although a few S100B–p53 interaction inhibitors have been identified via structure-based and ligand-based VS campaigns, reports of the discovery of other S100B–effector

Concluding remarks and perspective

S100B is overexpressed in several highly malignant cancers and exerts its biological function by physical interactions with its target molecules to induce cancer cell proliferation and metastasis. Up to now, one FDA-approved inhibitor (SBi1) has been repurposed for melanoma therapy and is in preclinical trials. Although several S100B inhibitors have been reported, most have targeted the S100B–p53 PPI for melanoma therapy. Hence, there is scope for the discovery of other S100B–effector protein

Acknowledgments

This work is supported by Hong Kong Baptist University (FRG2/17-18/003), the Health and Medical Research Fund (HMRF/14150561), the National Natural Science Foundation of China (21775131, China), the Hong Kong Baptist University Century Club Sponsorship Scheme 2019, the Interdisciplinary Research Matching Scheme (RC-IRMS/16-17/03), Interdisciplinary Research Clusters Matching Scheme (RC-IRCs/17-18/03), Collaborative Research Fund (C5026-16G), SKLEBA and HKBU Strategic Development Fund (

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