Allosteric Tuning of Caspase‐7: A Fragment‐Based Drug Discovery Approach

Vance, Nicholas R.; Gakhar, Lokesh; Spies, Maria

doi:10.1002/anie.201706959

Cited by 13 publications

(27 citation statements)

References 20 publications

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“…17 Unlike DICA and FICA, which binds irreversibly to caspase-3/7, compound-A reported by Feldman et al 28 interacts reversibly with the dimerization site of executioner caspase-7. Recently, Spies and co-workers, 37 using a fragment-based drug discovery approach, identified a series of compounds exhibiting allosteric inhibitory capabilities against caspase-7 (IC 50 values 637-8520 μM).…”

Section: Discussionmentioning

confidence: 99%

“…Unlike DICA and FICA, which binds irreversibly to caspase‐3/7, compound‐A reported by Feldman et al interacts reversibly with the dimerization site of executioner caspase‐7. Recently, Spies and co‐workers, using a fragment‐based drug discovery approach, identified a series of compounds exhibiting allosteric inhibitory capabilities against caspase‐7 (IC 50 values 637‐8520 μM). Two of these compounds share good structural similarity with 3 compounds tested in our study ( T c value 0.4‐0.7) and are found to occupy part of the allosteric pocket at the dimer interface in caspase‐7.…”

Section: Discussionmentioning

confidence: 99%

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Identification of FDA‐approved drugs as novel allosteric inhibitors of human executioner caspases

et al. 2018

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The regulation of apoptosis is a tightly coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted. Thus, we sought to identify FDA-approved drugs that could be repurposed as novel allosteric inhibitors of caspase-3/7. In this study, we virtually screened a catalog of FDA-approved drugs targeting an allosteric pocket located at the dimerization interface of caspase-3/7. From among the top-scoring hits we short-listed 5 compounds for experimental validation. Our enzymatic assays using recombinant caspase-3 suggested that 4 out of the 5 drugs effectively inhibited caspase-3 enzymatic activity in vitro with IC values ranging ~10-55 μM. Structural analysis of the docking poses show the 4 compounds forming specific non-covalent interactions at the allosteric pocket suggesting that these molecules could disrupt the adjacently-located active site. In summary, we report the identification of 4 novel non-peptide allosteric inhibitors of caspase-3/7 from among FDA-approved drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification of FDA‐approved drugs as novel allosteric inhibitors of human executioner caspases

et al. 2018

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“…This approximation causes a dramatic increase in the thrombin inactivation rate. HCII provides an extra interaction by binding of its N-terminus to thrombin ABE I. Fragment screening against caspase-7 identified two small molecule non-competitive inhibitors with potential for drug development [229]. X-ray crystallography showed allosteric binding at the caspase dimer interface, more than 17 Å removed from the active site.…”

Section: The Future Of Proteolysis-related Drug and Diagnostic Develomentioning

confidence: 99%

Proteases: Pivot Points in Functional Proteomics

Verhamme

Leonard

Perkins

2018

Functional Proteomics

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Proteases drive the life cycle of all proteins, ensuring the transportation and activation of newly minted, would-be proteins into their functional form while recycling spent or unneeded proteins. Far from their image as engines of protein digestion, proteases play fundamental roles in basic physiology and regulation at multiple levels of systems biology. Proteases are intimately associated with disease and modulation of proteolytic activity is the presumed target for successful therapeutics. “Proteases: Pivot Points in Functional Proteomics” examines the crucial roles of proteolysis across a wide range of physiological processes and diseases. The existing and potential impacts of proteolysis-related activity on drug and biomarker development are presented in detail. All told the decisive roles of proteases in four major categories comprising 23 separate sub-categories are addressed. Within this construct, 15 sets of subject-specific, tabulated data are presented that include identification of proteases, protease inhibitors, substrates and their actions. Said data are derived from and confirmed by over 300 references. Cross comparison of datasets indicates that proteases, their inhibitors/promoters and substrates intersect over a range of physiological processes and diseases, both chronic and pathogenic. Indeed, “Proteases: Pivot Points …” closes by dramatizing this very point through association of (pro)Thrombin and Fibrin(ogen) with: hemostasis, innate immunity, cardiovascular and metabolic disease, cancer, neurodegeneration and bacterial self-defense.

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“…Transient binding pockets are generally hard to predict and, as a matter of fact, have always been discovered in retrospect in structures of protein-ligand complexes as fortunate coincidence. Prominent examples for the retrospective discovery of transient binding pockets are caspase 7 (Vance, Gakhar, & Spies, 2017), γ-secretase (Kukar et al, 2008), diverse protein kinases (Liu et al, 2011;Wylie et al, 2017;Zhang et al, 2010), and also histone deacetylases (Bottomley et al, 2008;Burli et al, 2013;Hudson et al, 2015;KrennHrubec et al, 2007;Rumpf et al, 2015).…”

Section: Meyer-almesmentioning

confidence: 99%

Determination of the binding mechanism of histone deacetylase inhibitors

Meyer‐Almes

2018

Chem Biol Drug Des

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This article places its focus on methods and tools enabling the elucidation of the mechanism by which ligands, small‐molecule inhibitors, or substrates interact with zinc‐containing bacterial or human members of the histone deacetylase family (HDACs). These methods include biochemical and biophysical approaches and can be subdivided into equilibrium and kinetic methods. More information about the exact mode of action can be obtained by combining these methods with specific mutant variants of the enzymes and/or series of structural similar ligands. All available equilibrium and kinetic data including additional information from 3D structures of HDAC–ligand complexes can be beneficially combined in a data analysis procedure called Integrated Global‐Fit analysis eventually providing the most likely binding mechanism.

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Allosteric Tuning of Caspase‐7: A Fragment‐Based Drug Discovery Approach

Cited by 13 publications

References 20 publications

Identification of FDA‐approved drugs as novel allosteric inhibitors of human executioner caspases

Identification of FDA‐approved drugs as novel allosteric inhibitors of human executioner caspases

Proteases: Pivot Points in Functional Proteomics

Determination of the binding mechanism of histone deacetylase inhibitors

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