Imperial College London

DrElenaDe Vita

Faculty of Natural SciencesDepartment of Chemistry

Marie Skłodowska-Curie Fellow
 
 
 
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e.de-vita17 CV

 
 
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Molecular Sciences Research HubWhite City Campus

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Summary

 

Publications

Publication Type
Year
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16 results found

Zhang Q, Kounde C, Mondal M, Zhang L, Conole D, De Vita E, Fuchter M, Tate Eet al., 2022, Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs), Chemical Communications, ISSN: 1359-7345

Light-activable spatiotemporal control of PROTAC-induced protein degradation was achieved with novel arylazopyrazole photoswitchable PROTACs (AP-PROTACs). The use of a promiscuous kinase inhibitor in the design enables this unique photoswitchable PROTAC to selectively degrade four protein kinases together with on/off optical control using different wavelengths of light.

Journal article

Jamshidiha M, Lanyon-Hogg T, Sutherell C, Craven G, Tersa M, De Vita E, Brustur D, Perez-Doraldo I, Hassan S, Petracca R, Morgan R, Sanz-Hernández M, Norman J, Armstrong A, Mann D, Cota E, Tate Eet al., 2021, Identification of the first structurally validated covalent ligands of the small GTPase RAB27A, RSC Medicinal Chemistry, Vol: 13, Pages: 150-155, ISSN: 2632-8682

Rab27A is a small GTPase, which mediates transport and docking of secretory vesicles at the plasma membrane via protein–protein interactions (PPIs) with effector proteins. Rab27A promotes the growth and invasion of multiple cancer types such as breast, lung and pancreatic, by enhancing secretion of chemokines, metalloproteases and exosomes. The significant role of Rab27A in multiple cancer types and the minor role in adults suggest that Rab27A may be a suitable target to disrupt cancer metastasis. Similar to many GTPases, the flat topology of the Rab27A-effector PPI interface and the high affinity for GTP make it a challenging target for inhibition by small molecules. Reported co-crystal structures show that several effectors of Rab27A interact with the Rab27A SF4 pocket (‘WF-binding pocket’) via a conserved tryptophan–phenylalanine (WF) dipeptide motif. To obtain structural insight into the ligandability of this pocket, a novel construct was designed fusing Rab27A to part of an effector protein (fRab27A), allowing crystallisation of Rab27A in high throughput. The paradigm of KRas covalent inhibitor development highlights the challenge presented by GTPase proteins as targets. However, taking advantage of two cysteine residues, C123 and C188, that flank the WF pocket and are unique to Rab27A and Rab27B among the >60 Rab family proteins, we used the quantitative Irreversible Tethering (qIT) assay to identify the first covalent ligands for native Rab27A. The binding modes of two hits were elucidated by co-crystallisation with fRab27A, exemplifying a platform for identifying suitable lead fragments for future development of competitive inhibitors of the Rab27A-effector interaction interface, corroborating the use of covalent libraries to tackle challenging targets.

Journal article

Yoon H, Triplet EM, Simon WL, Choi C-I, Kleppe LS, De Vita E, Miller AK, Scarisbrick IAet al., 2021, Blocking Kallikrein 6 promotes developmental myelination, GLIA, Vol: 70, Pages: 430-450, ISSN: 0894-1491

Journal article

Santamaria S, Buemi F, Nuti E, Cuffaro D, De Vita E, Tuccinardi T, Rossello A, Howell S, Mehmood S, Snijders AP, de Groot Ret al., 2021, Development of a fluorogenic ADAMTS-7 substrate, Journal of Enzyme Inhibition and Medicinal Chemistry, Vol: 36, ISSN: 1475-6366

The extracellular protease ADAMTS-7 has been identified as a potential therapeutic target in atherosclerosis and associated diseases such as coronary artery disease (CAD). However, ADAMTS-7 inhibitors have not been reported so far. Screening of inhibitors has been hindered by the lack of a suitable peptide substrate and, consequently, a convenient activity assay. Here we describe the first fluorescence resonance energy transfer (FRET) substrate for ADAMTS-7, ATS7FP7. ATS7FP7 was used to measure inhibition constants for the endogenous ADAMTS-7 inhibitor, TIMP-4, as well as two hydroxamate-based zinc chelating inhibitors. These inhibition constants match well with IC50 values obtained with our SDS-PAGE assay that uses the N-terminal fragment of latent TGF-β–binding protein 4 (LTBP4S-A) as a substrate. Our novel fluorogenic substrate ATS7FP7 is suitable for high throughput screening of ADAMTS-7 inhibitors, thus accelerating translational studies aiming at inhibition of ADAMTS-7 as a novel treatment for cardiovascular diseases such as atherosclerosis and CAD.

Journal article

De Vita E, Lucy D, Tate EW, 2021, Beyond targeted protein degradation: LD.ATTECs clear cellular lipid droplets, CELL RESEARCH, Vol: 31, Pages: 945-946, ISSN: 1001-0602

Journal article

Lovell S, Zhang L, Kryza T, Neodo A, Bock N, De Vita E, Williams E, Engelsberger E, Xu C, Bakker A, Maneiro M, Tanaka R, Bevan C, Clements J, Tate Eet al., 2021, A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer, Journal of the American Chemical Society, Vol: 143, Pages: 8911-8924, ISSN: 0002-7863

Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network (the KLK activome) with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors enabling simultaneous orthogonal analysis of KLK2, KLK3, and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Importantly, we identifed a significant decoupling of KLK activity and abundance and suggest that KLK proteolysis should be considered as an additional parameter, along with the PSA blood test, for accurate PCa diagnosis and monitoring. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP), we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs, we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.

Journal article

Tate E, 2021, PROTACs, molecular glues and bifunctionals from bench to bedside: Unlocking the clinical potential of catalytic drugs, Progress in medicinal chemistry, ISSN: 0079-6468

Journal article

Lovell S, Zhang L, Kryza T, Neodo A, Bock N, Williams ED, Engelsberger E, Xu C, Bakker AT, De Vita E, Maneiro M, Tanaka RJ, Bevan CL, Clements JA, Tate EWet al., 2021, A suite of activity-based probes to dissect the KLK activome in drug-resistant prostate cancer

<jats:title>Abstract</jats:title><jats:p>Kallikrein-related peptidases (KLKs) are a family of secreted serine proteases, which form a network – the KLK activome – with an important role in proteolysis and signaling. In prostate cancer (PCa), increased KLK activity promotes tumor growth and metastasis through multiple biochemical pathways, and specific quantification and tracking of changes in the KLK activome could contribute to validation of KLKs as potential drug targets. Herein we report a technology platform based on novel activity-based probes (ABPs) and inhibitors with unprecedented potency and selectivity enabling simultaneous orthogonal analysis of KLK2, KLK3 and KLK14 activity in hormone-responsive PCa cell lines and tumor homogenates. Using selective inhibitors and multiplexed fluorescent activity-based protein profiling (ABPP) we dissect the KLK activome in PCa cells and show that increased KLK14 activity leads to a migratory phenotype. Furthermore, using biotinylated ABPs we show that active KLK molecules are secreted into the bone microenvironment by PCa cells following stimulation by osteoblasts suggesting KLK-mediated signaling mechanisms could contribute to PCa metastasis to bone. Together our findings show that ABPP is a powerful approach to dissect dysregulation of the KLK activome as a promising and previously underappreciated therapeutic target in advanced PCa.</jats:p>

Journal article

De Vita E, 2020, 10 years into the resurgence of covalent drugs, FUTURE MEDICINAL CHEMISTRY, Vol: 13, Pages: 193-210, ISSN: 1756-8919

Journal article

De Vita E, Maneiro M, Tate EW, 2020, The missing link between (Un)druggable and degradable KRAS, ACS Central Science, Vol: 6, Pages: 1281-1284, ISSN: 2374-7943

Journal article

De Vita E, Smits N, van den Hurk H, Beck EM, Hewitt J, Baillie G, Russell E, Pannifer A, Hamon V, Morrison A, McElroy SP, Jones P, Ignatenko NA, Gunkel N, Miller AKet al., 2019, Synthesis and structure-activity relationships of N-(4-Benzamidino)-oxazolidinones: potent and selective inhibitors of kallikrein-related peptidase 6, ChemMedChem, Vol: 15, Pages: 79-95, ISSN: 0014-827X

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high-throughput screen within the European Lead Factory program. Structure-guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)-3-(4-carbamimidoylphenyl)-N-((S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) and 34 ((5R)-3-(6-carbamimidoylpyridin-3-yl)-N-((1S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) have single-digit nanomolar potency against KLK6, with over 25-fold and 100-fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6-dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.

Journal article

De Vita E, Smits N, van den Hurk H, Beck EM, Hewitt J, Baillie G, Russell E, Pannifer A, Hamon V, Morrison A, McElroy SP, Jones P, Ignatenko NA, Gunkel N, Miller AKet al., 2019, Synthesis and Structure–Activity Relationships of N-(4-Benzamidino)-Oxazolidinones–Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6, Publisher: American Chemical Society (ACS)

<jats:p>Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high-throughput screen within the European Lead Factory program. Structure-guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors <jats:bold>32</jats:bold> and<jats:bold> 34</jats:bold> have single digit nanomolar potency against KLK6, with over 25-fold and 100-fold selectivity, respectively, against the closely related enzyme trypsin. The most potent compound, <jats:bold>32</jats:bold>, effectively reduces KLK6-dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of <jats:bold>32</jats:bold> make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.</jats:p>

Working paper

D'Andrea F, Nuti E, Becherini S, Cuffaro D, Husanu E, Camodeca C, De Vita E, Zocchi MR, Poggi A, D'Arrigo C, Cappello V, Gemmi M, Nencetti S, Chiappe C, Rossello Aet al., 2019, Design and Synthesis of Ionic Liquid-Based Matrix Metalloproteinase Inhibitors (MMPIs): A Simple Approach to Increase Hydrophilicity and to Develop MMPI-Coated Gold Nanoparticles, CHEMMEDCHEM, Vol: 14, Pages: 686-698, ISSN: 1860-7179

Journal article

De Vita E, Schuler P, Lovell S, Lohbeck J, Kullmann S, Rabinovich E, Sananes A, Hessling B, Hamon V, Papo N, Hess J, Tate EW, Gunkel N, Miller AKet al., 2018, Depsipeptides Featuring a Neutral P1 Are Potent Inhibitors of Kallikrein-Related Peptidase 6 with On-Target Cellular Activity, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 61, Pages: 8859-8874, ISSN: 0022-2623

Journal article

Sananes A, Cohen I, Shahar A, Hockla A, De Vita E, Miller AK, Radisky ES, Papo Net al., 2018, A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 293, Pages: 12663-12680

Journal article

Longuespee R, Wefers AK, De Vita E, Miller AK, Reuss DE, Wick W, Herold-Mende C, Kriegsmann M, Schirmacher P, von Deimling A, Pusch Set al., 2018, Rapid detection of 2-hydroxyglutarate in frozen sections of IDH mutant tumors by MALDI-TOF mass spectrometry, Acta Neuropathologica Communications, Vol: 6, Pages: 1-9, ISSN: 2051-5960

All isocitrate dehydrogenase (IDH) mutant solid neoplasms exhibit highly elevated levels of D-2-hydroxyglutarate (D-2HG). Detection of 2HG in tumor tissues currently is performed by gas or liquid chromatography-mass spectrometry (GC- or LC-MS) or biochemical detection. While these methods are highly accurate, a considerable amount of time for tissue preparation and a relatively high amount of tissue is required for testing. We here present a rapid approach to detect 2HG in brain tumor tissue based on matrix-assisted laser desorption ionization - time of flight mass spectrometry (MALDI-TOF). We analyzed 26 brain tumor samples with known IDH1 or IDH2 mutation and compared readouts to those from 28 brain tumor samples of wildtype IDH status. IDH mutant samples exhibited a clear positive signal for 2HG which was not observed in any of the IDH wildtype tumors. Our analytical pipeline allowed for 2HG detection in less than 5 min. Data were validated by determining 2HG levels in all tissues with a biochemical assay. In conclusion, we developed a protocol for rapid detection of 2HG levels and illustrate the possibility to use MALDI-TOF for the detection of metabolites on frozen tissue sections in a diagnostic setting.

Journal article

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