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Article ; Online: Mixture-Based Screening of Focused Combinatorial Libraries by NMR: Application to the Antiapoptotic Protein hMcl-1.

Alboreggia, Giulia / Udompholkul, Parima / Baggio, Carlo / Pellecchia, Maurizio

2023 Volume 66, Issue 14, Page(s) 10108–10118

Abstract: We report on an innovative ligand discovery strategy based on protein NMR-based screening of a combinatorial library of ∼125,000 compounds that was arranged in 96 distinct mixtures. Using sensitive solution protein NMR spectroscopy and chemical ... ...

Abstract	We report on an innovative ligand discovery strategy based on protein NMR-based screening of a combinatorial library of ∼125,000 compounds that was arranged in 96 distinct mixtures. Using sensitive solution protein NMR spectroscopy and chemical perturbation-based screening followed by an iterative synthesis, deconvolutions, and optimization strategy, we demonstrate that the approach could be useful in the identification of initial binding molecules for difficult drug targets, such as those involved in protein-protein interactions. As an application, we will report novel agents targeting the Bcl-2 family protein hMcl-1. The approach is of general applicability and could be deployed as an effective screening strategy for de novo identification of ligands, particularly when tackling targets involved in protein-protein interactions.
MeSH term(s)	Combinatorial Chemistry Techniques/methods ; Proteins/chemistry ; Magnetic Resonance Spectroscopy/methods ; Magnetic Resonance Imaging ; Ligands ; Protein Binding
Chemical Substances	Proteins ; Ligands
Language	English
Publishing date	2023-07-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01073
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Article ; Online: Targefrin: A Potent Agent Targeting the Ligand Binding Domain of EphA2.

Baggio, Carlo / Udompholkul, Parima / Gambini, Luca / Pellecchia, Maurizio

Journal of medicinal chemistry

2022 Volume 65, Issue 22, Page(s) 15443–15456

Abstract: Overexpression of the receptor tyrosine kinase EphA2 is invariably associated with poor prognosis and development of aggressive metastatic cancers. Guided by our recently solved X-ray structure of the complex between an agonistic peptide and EphA2-LBD, ... ...

Abstract	Overexpression of the receptor tyrosine kinase EphA2 is invariably associated with poor prognosis and development of aggressive metastatic cancers. Guided by our recently solved X-ray structure of the complex between an agonistic peptide and EphA2-LBD, we report on a novel agent, targefrin, that binds to EphA2-LBD with a 21 nM dissociation constant by isothermal titration calorimetry and presents an IC
MeSH term(s)	Animals ; Humans ; Mice ; Cell Line ; Ligands ; Peptides/pharmacology ; Receptor Protein-Tyrosine Kinases ; Receptor, EphA2/drug effects ; Receptor, EphA2/metabolism ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology
Chemical Substances	Ligands ; Peptides ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1) ; Receptor, EphA2 (EC 2.7.10.1) ; Antineoplastic Agents
Language	English
Publishing date	2022-11-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.2c01391
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Article ; Online: Antagonists of protein-protein interactions made easy?

Pellecchia, Maurizio

Journal of medicinal chemistry

2012 Volume 56, Issue 1, Page(s) 13–14

MeSH term(s)	Antineoplastic Agents/chemistry ; Humans ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors ; Small Molecule Libraries/chemistry
Chemical Substances	Antineoplastic Agents ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; Small Molecule Libraries
Language	English
Publishing date	2012-12-24
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm301837n
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Article ; Online: Lysine Covalent Antagonists of Melanoma Inhibitors of Apoptosis Protein.

Udompholkul, Parima / Baggio, Carlo / Gambini, Luca / Alboreggia, Giulia / Pellecchia, Maurizio

Journal of medicinal chemistry

2021 Volume 64, Issue 21, Page(s) 16147–16158

Abstract: We have recently reported on Lys-covalent agents that, based on aryl-sulfonyl fluorides, were designed to target binding site Lys 311 in the X-linked inhibitor of apoptosis protein (XIAP). Similar to XIAP, melanoma-IAP (ML-IAP), a less well-characterized ...

Abstract	We have recently reported on Lys-covalent agents that, based on aryl-sulfonyl fluorides, were designed to target binding site Lys 311 in the X-linked inhibitor of apoptosis protein (XIAP). Similar to XIAP, melanoma-IAP (ML-IAP), a less well-characterized IAP family protein, also presents a lysine residue (Lys 135), which is in a position equivalent to that of Lys 311 of XIAP. On the contrary, two other members of the IAP family, namely, cellular-IAPs (cIAP1 and cIAP2), present a glutamic acid residue in that position. Hence, in the present work, we describe the derivation and characterization of the very first potent ML-IAP Lys-covalent inhibitor with cellular activity. The agent can be used as a pharmacological tool to further validate ML-IAP as a drug target and eventually for the development of ML-IAP-targeted therapeutics.
MeSH term(s)	Cell Line, Tumor ; Humans ; Inhibitor of Apoptosis Proteins/antagonists & inhibitors ; Inhibitor of Apoptosis Proteins/chemistry ; Lysine/chemistry ; Melanoma/pathology
Chemical Substances	Inhibitor of Apoptosis Proteins ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2021-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c01459
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Article ; Online: Characterization of a Potent and Orally Bioavailable Lys-Covalent Inhibitor of Apoptosis Protein (IAP) Antagonist.

Udompholkul, Parima / Garza-Granados, Ana / Alboreggia, Giulia / Baggio, Carlo / McGuire, Jack / Pegan, Scott D / Pellecchia, Maurizio

Journal of medicinal chemistry

2023 Volume 66, Issue 12, Page(s) 8159–8169

Abstract: We have recently reported on the use of aryl-fluorosulfates in designing water- and plasma-stable agents that covalently target Lys, Tyr, or His residues in the BIR3 domain of the inhibitor of the apoptosis protein (IAP) family. Here, we report further ... ...

Abstract	We have recently reported on the use of aryl-fluorosulfates in designing water- and plasma-stable agents that covalently target Lys, Tyr, or His residues in the BIR3 domain of the inhibitor of the apoptosis protein (IAP) family. Here, we report further structural, cellular, and pharmacological characterizations of this agent, including the high-resolution structure of the complex between the Lys-covalent agent and its target, the BIR3 domain of X-linked IAP (XIAP). We also compared the cellular efficacy of the agent in two-dimensional (2D) and three-dimensional (3D) cell cultures, side by side with the clinical candidate reversible IAP inhibitor LCL161. Finally,
MeSH term(s)	Inhibitor of Apoptosis Proteins ; Protein Binding ; X-Linked Inhibitor of Apoptosis Protein/metabolism ; Apoptosis
Chemical Substances	Inhibitor of Apoptosis Proteins ; X-Linked Inhibitor of Apoptosis Protein
Language	English
Publishing date	2023-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c00467
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Article ; Online: Fragment-based drug discovery takes a virtual turn.

Pellecchia, Maurizio

Nature chemical biology

2009 Volume 5, Issue 5, Page(s) 274–275

MeSH term(s)	Crystallography, X-Ray ; Drug Discovery ; Models, Molecular
Language	English
Publishing date	2009-04-17
Publishing country	United States
Document type	Comment ; News
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/nchembio0509-274
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Article ; Online: NMR-based approaches for the identification and optimization of inhibitors of protein-protein interactions.

Barile, Elisa / Pellecchia, Maurizio

Chemical reviews

2014 Volume 114, Issue 9, Page(s) 4749–4763

MeSH term(s)	Biophysics ; Drug Design ; Ligands ; Magnetic Resonance Spectroscopy/methods ; Protein Binding/drug effects ; Proteins/antagonists & inhibitors ; Proteins/chemistry
Chemical Substances	Ligands ; Proteins
Language	English
Publishing date	2014-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	207949-5
ISSN	1520-6890 ; 0009-2665
ISSN (online)	1520-6890
ISSN	0009-2665
DOI	10.1021/cr500043b
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Article: Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents.

Salem, Ahmed F / Gambini, Luca / Udompholkul, Parima / Baggio, Carlo / Pellecchia, Maurizio

Pharmaceuticals (Basel, Switzerland)

2020 Volume 13, Issue 5

Abstract: Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of ... ...

Abstract	Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of dimeric compounds at the structural, biochemical, and cellular level. In particular, we propose a structural model for the mechanism of receptor activation by dimeric agents and characterize the effect of most potent compounds in inducing EphA2 activation and degradation in a pancreatic cancer cell line. These cellular studies indicate that the pro-migratory effects induced by the receptor can be reversed in EphA2 knockout cells, by treatment with either a dimeric natural ligand (ephrinA1-Fc), or by our synthetic agonistic dimers. Based on these data we conclude that the proposed agents hold great potential as possible therapeutics in combination with standard of care, where these could help suppressing a major driver for cell migration and tumor metastases. Finally, we also found that, similar to ephrinA1-Fc, dimeric agents cause a sustained internalization of the EphA2 receptor, hence, with proper derivatizations, these could also be used to deliver chemotherapy selectively to pancreatic tumors.
Language	English
Publishing date	2020-05-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph13050090
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Article ; Online: Therapeutic Targeting of MMP-12 for the Treatment of Chronic Obstructive Pulmonary Disease.

Baggio, Carlo / Velazquez, Jalene V / Fragai, Marco / Nordgren, Tara M / Pellecchia, Maurizio

Journal of medicinal chemistry

2020 Volume 63, Issue 21, Page(s) 12911–12920

Abstract: Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically ...

Abstract	Chronic obstructive pulmonary disease (COPD) is a lung disorder characterized by progressive airflow obstruction associated with inflammation and emphysema, and it is currently one of the leading causes of death worldwide. Recent studies with genetically engineered mice reported that during pulmonary inflammation, basophil-derived interleukin-4 can act on lung-infiltrating monocytes causing aberrant expression of the matrix metalloproteinase-12 (MMP-12). MMP-12 activity in turn causes the destruction of alveolar walls leading to emphysema, making it potentially a valid target for pharmacological intervention. Using nuclear magnetic resonance (NMR)- and structure-based optimizations, the current study reports on the optimized novel, potent, and selective MMP-12 inhibitors with single-digit nanomolar affinity
MeSH term(s)	Animals ; Binding Sites ; Crystallography, X-Ray ; Disease Models, Animal ; Emphysema/drug therapy ; Emphysema/etiology ; Half-Life ; Humans ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/metabolism ; Matrix Metalloproteinase 12/chemistry ; Matrix Metalloproteinase 12/metabolism ; Matrix Metalloproteinase Inhibitors/chemistry ; Matrix Metalloproteinase Inhibitors/pharmacokinetics ; Matrix Metalloproteinase Inhibitors/therapeutic use ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Molecular Dynamics Simulation ; Nuclear Magnetic Resonance, Biomolecular ; Pancreatic Elastase/metabolism ; Peptides/genetics ; Peptides/metabolism ; Peptides/therapeutic use ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Pulmonary Disease, Chronic Obstructive/pathology ; Structure-Activity Relationship
Chemical Substances	Isoenzymes ; Matrix Metalloproteinase Inhibitors ; Peptides ; Pancreatic Elastase (EC 3.4.21.36) ; Matrix Metalloproteinase 12 (EC 3.4.24.65)
Language	English
Publishing date	2020-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c01285
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Article ; Online: Stability and Cell Permeability of Sulfonyl Fluorides in the Design of Lys-Covalent Antagonists of Protein-Protein Interactions.

Gambini, Luca / Udompholkul, Parima / Salem, Ahmed F / Baggio, Carlo / Pellecchia, Maurizio

ChemMedChem

2020 Volume 15, Issue 22, Page(s) 2176–2184

Abstract: Recently we reported on aryl-fluorosulfates as possible stable and effective electrophiles for the design of lysine covalent, cell permeable antagonists of protein-protein interactions (PPIs). Here we revisit the use of aryl-sulfonyl fluorides as Lys- ... ...

Abstract	Recently we reported on aryl-fluorosulfates as possible stable and effective electrophiles for the design of lysine covalent, cell permeable antagonists of protein-protein interactions (PPIs). Here we revisit the use of aryl-sulfonyl fluorides as Lys-targeting moieties, incorporating these electrophiles in XIAP (X-linked inhibitor of apoptosis protein) targeting agents. We evaluated stability in buffer and reactivity with Lys311 of XIAP of various aryl-sulfonyl fluorides using biochemical and biophysical approaches, including displacement assays, mass spectrometry, SDS gel electrophoresis, and denaturation thermal shift measurements. To assess whether these modified electrophilic "warheads" can also react with Tyr, we repeated these evaluations with a Lys311Tyr XIAP mutant. Using a direct cellular assay, we could demonstrate that selected agents are cell permeable and interact covalently with their intended target in cell. These results suggest that certain substituted aryl-sulfonyl fluorides can be useful Lys- or Tyr-targeting electrophiles for the design of covalent pharmacological tools or even future therapeutics targeting protein-protein interactions.
MeSH term(s)	Drug Design ; HEK293 Cells ; Humans ; Lysine/chemistry ; Lysine/pharmacology ; Molecular Structure ; Permeability/drug effects ; Protein Binding/drug effects ; Sulfinic Acids/chemical synthesis ; Sulfinic Acids/chemistry ; Sulfinic Acids/pharmacology ; X-Linked Inhibitor of Apoptosis Protein/antagonists & inhibitors
Chemical Substances	Sulfinic Acids ; X-Linked Inhibitor of Apoptosis Protein ; XIAP protein, human ; sulfuryl fluoride (64B59K7U6Q) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2020-10-13
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2218496-X
ISSN	1860-7187 ; 1860-7179
ISSN (online)	1860-7187
ISSN	1860-7179
DOI	10.1002/cmdc.202000355
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