Regulation of cadherin dimerization by chemical fragments as a trigger to inhibit cell adhesion

AbstractMany cadherin family proteins are associated with diseases such as cancer. Since cell adhesion requires homodimerization of cadherin molecules, a small-molecule regulator of dimerization would have therapeutic potential. Herein, we describe identification of a P-cadherin-specific chemical fragment that inhibits P-cadherin-mediated cell adhesion. Although the identified molecule is a fragment compound, it binds to a cavity of P-cadherin that has not previously been targeted, indirectly prevents formation of hydrogen bonds necessary for formation of an intermediate called the X dimer and thus modulates the process of X dimerization. Our findings will impact on a strategy for regulation of protein-protein interactions and stepwise assembly of protein complexes using small molecules.

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On-rate modulation of cadherin interactions by chemical fragments

10.1101/2020.08.30.274647 ◽

2020 ◽

Author(s):

Akinobu Senoo ◽

Sho Ito ◽

Satoru Nagatoishi ◽

Yutaro Saito ◽

Go Ueno ◽

...

Keyword(s):

Cell Adhesion ◽

Small Molecules ◽

Protein Interactions ◽

Therapeutic Potential ◽

Protein Complexes ◽

Protein Protein Interactions ◽

Specific Chemical ◽

Rate Modulation ◽

Stepwise Assembly ◽

Kinetic Regulation

AbstractMany cadherin family proteins are associated with diseases such as cancer. Since cell adhesion requires homodimerization of cadherin molecules, a small-molecule regulator of dimerization would have therapeutic potential. Herein, we describe identification of a P-cadherin-specific chemical fragment that inhibits P-cadherin-mediated cell adhesion. Although the identified molecule is a fragment compound, it binds to a cavity of P-cadherin that has not previously been targeted, indirectly prevents formation of hydrogen bonds necessary for formation of an intermediate called the X dimer and thus modulates the on-rate of X dimerization. Our findings will impact on a strategy for kinetic regulation of protein-protein interactions and stepwise assembly of protein complexes using small molecules.

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Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

Nature Communications ◽

10.1038/s41467-019-13616-1 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 12

Author(s):

James O’Connell ◽

John Porter ◽

Boris Kroeplien ◽

Tim Norman ◽

Stephen Rapecki ◽

...

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Protein Interactions ◽

General Mechanism ◽

Protein Protein Interactions ◽

Biologic Drugs ◽

Small Molecule Drugs ◽

Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

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Insights on small-molecules inhibitors and protein-protein interactions of the T4SS

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314094170 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C582-C582

Author(s):

Ingrid Um Nlend ◽

Christian Baron

Keyword(s):

Small Molecules ◽

Virulence Factor ◽

Protein Interactions ◽

Protein Complexes ◽

Cell Envelope ◽

Gram Negative Bacteria ◽

Protein Protein Interactions ◽

Excellent Model ◽

Assembly Factor ◽

Multiple Interactions

ABSTRACT: Bacterial T4SS are complexes, constituted of 8 to 12 conserved proteins, used by many gram-negative bacteria for the translocation of proteins and DNA-protein complexes as well as for the transportation of DNA-protein complexes across their cell envelope. T4SS are excellent model targets for the development of antivirulence drugs as it is an essential virulence factor for many bacterial pathogens, such as Brucella. Antivirulence drugs that deprive the pathogen of its essential virulence factor, the T4SS, would constitute alternatives to or enhancements of current antibiotic treatment. VirB8, a conserved assembly factor in T4SS forms dimers that are very important for T4SS function in these pathogens. Due to its multiple interactions, VirB8 is an excellent model for the analysis of assembly factors but also a possible target for drugs that could target its protein–protein interactions, which would disarm bacteria by depriving them of their essential virulence functions.

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Targeting epigenetic protein–protein interactions with small-molecule inhibitors

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0082 ◽

2020 ◽

Vol 12 (14) ◽

pp. 1305-1326 ◽

Cited By ~ 1

Author(s):

Brian M Linhares ◽

Jolanta Grembecka ◽

Tomasz Cierpicki

Keyword(s):

Small Molecules ◽

Small Molecule ◽

Protein Interactions ◽

Small Molecule Inhibitors ◽

Chemical Space ◽

Scaffolding Proteins ◽

Protein Protein Interactions ◽

Post Translational Modifications ◽

Inhibitor Development ◽

Interdisciplinary Approaches

Epigenetic protein–protein interactions (PPIs) play essential roles in regulating gene expression, and their dysregulations have been implicated in many diseases. These PPIs are comprised of reader domains recognizing post-translational modifications on histone proteins, and of scaffolding proteins that maintain integrities of epigenetic complexes. Targeting PPIs have become focuses for development of small-molecule inhibitors and anticancer therapeutics. Here we summarize efforts to develop small-molecule inhibitors targeting common epigenetic PPI domains. Potent small molecules have been reported for many domains, yet small domains that recognize methylated lysine side chains on histones are challenging in inhibitor development. We posit that the development of potent inhibitors for difficult-to-prosecute epigenetic PPIs may be achieved by interdisciplinary approaches and extensive explorations of chemical space.

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Probing conformational hotspots for the recognition and intervention of protein complexes by lysine reactivity profiling

Chemical Science ◽

10.1039/d0sc05330a ◽

2021 ◽

Author(s):

Zheyi Liu ◽

Wenxiang Zhang ◽

Binwen Sun ◽

Yaolu Ma ◽

Min He ◽

...

Keyword(s):

Mass Spectrometry ◽

Small Molecule ◽

Protein Interactions ◽

Isotope Labeling ◽

Protein Complexes ◽

Protein Protein Interactions ◽

Active Compounds

A mass spectrometry-based two-step isotope labeling-lysine reactivity profiling strategy is developed to probe the molecular details of protein–protein interactions and evaluate the conformational interventions by small-molecule active compounds.

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Specific Inhibition of HIF Activity: Can Peptides Lead the Way?

Cancers ◽

10.3390/cancers13030410 ◽

2021 ◽

Vol 13 (3) ◽

pp. 410

Author(s):

Ilias Mylonis ◽

Georgia Chachami ◽

George Simos

Keyword(s):

Transcription Factors ◽

Small Molecules ◽

Protein Interactions ◽

Cellular Response ◽

Therapeutic Potential ◽

Special Focus ◽

Hypoxia Inducible Factors ◽

Protein Protein Interactions ◽

Pharmacological Agents ◽

Specific Manner

Reduced oxygen availability (hypoxia) is a characteristic of many disorders including cancer. Central components of the systemic and cellular response to hypoxia are the Hypoxia Inducible Factors (HIFs), a small family of heterodimeric transcription factors that directly or indirectly regulate the expression of hundreds of genes, the products of which mediate adaptive changes in processes that include metabolism, erythropoiesis, and angiogenesis. The overexpression of HIFs has been linked to the pathogenesis and progression of cancer. Moreover, evidence from cellular and animal models have convincingly shown that targeting HIFs represents a valid approach to treat hypoxia-related disorders. However, targeting transcription factors with small molecules is a very demanding task and development of HIF inhibitors with specificity and therapeutic potential has largely remained an unattainable challenge. Another promising approach to inhibit HIFs is to use peptides modelled after HIF subunit domains known to be involved in protein–protein interactions that are critical for HIF function. Introduction of these peptides into cells can inhibit, through competition, the activity of endogenous HIFs in a sequence and, therefore also isoform, specific manner. This review summarizes the involvement of HIFs in cancer and the approaches for targeting them, with a special focus on the development of peptide HIF inhibitors and their prospects as highly-specific pharmacological agents.

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Small-molecule modulation of p53 protein-protein interactions

Biological Chemistry ◽

10.1515/hsz-2019-0405 ◽

2020 ◽

Vol 401 (8) ◽

pp. 921-931 ◽

Cited By ~ 1

Author(s):

Ave Kuusk ◽

Helen Boyd ◽

Hongming Chen ◽

Christian Ottmann

Keyword(s):

Tumor Suppressor ◽

Small Molecules ◽

Small Molecule ◽

Protein Interactions ◽

P53 Protein ◽

Tumor Suppressor Protein ◽

Protein Protein Interactions ◽

Mdm2 Protein ◽

Protein Protein Interaction ◽

Altered Proteins

AbstractSmall-molecule modulation of protein-protein interactions (PPIs) is a very promising but also challenging area in drug discovery. The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. In this review, we give an overview of 14-3-3 interactions with p53, explain isoform specific stabilization of the tumor suppressor protein, explore the approach of stabilizing the 14-3-3σ-p53 complex and summarize some promising small molecules inhibiting the p53-MDM2 protein-protein interaction.

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Protein–protein interactions as targets for small-molecule therapeutics in cancer

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399408000641 ◽

2008 ◽

Vol 10 ◽

Cited By ~ 57

Author(s):

Alex W. White ◽

Andrew D. Westwell ◽

Ghali Brahemi

Keyword(s):

Drug Design ◽

Small Molecule ◽

Protein Interactions ◽

Therapeutic Potential ◽

Drug Binding ◽

Protein Protein Interactions ◽

Small Molecule Inhibition ◽

Conventional Drug ◽

Initial Identification ◽

Small Molecule Therapeutics

Small-molecule inhibition of the direct protein–protein interactions that mediate many important biological processes is an emerging and challenging area in drug design. Conventional drug design has mainly focused on the inhibition of a single protein, usually an enzyme or receptor, since these proteins often contain a clearly defined ligand-binding site with which a small-molecule drug can be designed to interact. Designing a small molecule to bind to a protein–protein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable protein–protein interactions, the surface area of the interface (it is often large), and the location of ‘hot spots’ (small regions suitable for drug binding). This article reviews the general approach to designing inhibitors of protein–protein interactions, and then focuses on recent advances in the use of small molecules targeted against a variety of protein–protein interactions that have therapeutic potential for cancer.

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14-3-3 and its binding partners are regulators of protein–protein interactions during spermatogenesis

Journal of Endocrinology ◽

10.1677/joe-09-0041 ◽

2009 ◽

Vol 202 (3) ◽

pp. 327-336 ◽

Cited By ~ 33

Author(s):

Shengyi Sun ◽

Elissa W P Wong ◽

Michelle W M Li ◽

Will M Lee ◽

C Yan Cheng

Keyword(s):

Cell Adhesion ◽

Protein Interactions ◽

Protein Complexes ◽

Morphological Changes ◽

Regulatory Protein ◽

Cell Movement ◽

Cytoskeletal Proteins ◽

Seminiferous Epithelium ◽

Protein Protein Interactions ◽

Binding Partners

During spermatogenesis, spermiation takes place at the adluminal edge of the seminiferous epithelium at stage VIII of the epithelial cycle during which fully developed spermatids (i.e. spermatozoa) detach from the epithelium in adult rat testes. This event coincides with the migration of preleptotene/leptotene spermatocytes across the blood–testis barrier from the basal to the apical (or adluminal) compartment. At stage XIV of the epithelial cycle, Pachytene spermatocytes (diploid, 2n) differentiate into diplotene spermatocytes (tetraploid, 4n) in the apical compartment of the epithelium, which begin meiosis I to be followed by meiosis II to form spermatids (haploid, 1n) at stage XIV of the epithelial cycle. These spermatids, in turn, undergo extensive morphological changes and traverse the seminiferous epithelium until they differentiate into elongated spermatids. Thus, there are extensive changes at the Sertoli–Sertoli and Sertoli–germ cell interface via protein ‘coupling’ and ‘uncoupling’ between cell adhesion protein complexes, as well as changes in interactions between integral membrane proteins and their peripheral adaptors, regulatory protein kinases and phosphatases, and the cytoskeletal proteins. These precisely coordinated protein–protein interactions affect cell adhesion and cell movement. In this review, we focus on the 14-3-3 protein family, whose members have different binding partners in the seminiferous epithelium. Recent studies have illustrated that 14-3-3 affects protein–protein interactions in the seminiferous epithelium, and regulates cell adhesion possibly via its effects on intracellular protein trafficking and cell-polarity proteins. This review provides a summary on the latest findings regarding the role of 14-3-3 family of proteins and their potential implications on spermatogenesis. We also highlight research areas that deserve attentions by investigators.

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