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Article: Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond.

Serafim, Ricardo A M / Gehringer, Matthias / Borsari, Chiara

2024 Volume 17, Issue 2

Abstract: Covalent inhibitors have experienced a revival in medicinal chemistry and chemical biology in recent decades [ ... ]. ...

Abstract	Covalent inhibitors have experienced a revival in medicinal chemistry and chemical biology in recent decades [...].
Language	English
Publishing date	2024-02-05
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph17020206
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Article ; Online: Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update.

Hillebrand, Laura / Liang, Xiaojun Julia / Serafim, Ricardo A M / Gehringer, Matthias

Journal of medicinal chemistry

2024

Abstract: Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with a variety of new targeted covalent drugs having been approved in recent years. A key feature of such molecules is an intrinsically reactive group, ...

Abstract	Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with a variety of new targeted covalent drugs having been approved in recent years. A key feature of such molecules is an intrinsically reactive group, typically a weak electrophile, which enables the irreversible or reversible formation of a covalent bond with a specific amino acid of the target protein. This reactive group, often called the "warhead", is a critical determinant of the ligand's activity, selectivity, and general biological properties. In 2019, we summarized emerging and re-emerging warhead chemistries to target cysteine and other amino acids (Gehringer, M.; Laufer, S. A.
Language	English
Publishing date	2024-05-06
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.3c01825
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Article ; Online: Chemical Probes for Understudied Kinases: Challenges and Opportunities.

Serafim, Ricardo A M / Elkins, Jonathan M / Zuercher, William J / Laufer, Stefan A / Gehringer, Matthias

Journal of medicinal chemistry

2021 Volume 65, Issue 2, Page(s) 1132–1170

Abstract: Over 20 years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated ... ...

Abstract	Over 20 years after the approval of the first-in-class protein kinase inhibitor imatinib, the biological function of a significant fraction of the human kinome remains poorly understood while most research continues to be focused on few well-validated targets. Given the strong genetic evidence for involvement of many kinases in health and disease, the understudied fraction of the kinome holds a large and unexplored potential for future therapies. Specific chemical probes are indispensable tools to interrogate biology enabling proper preclinical validation of novel kinase targets. In this Perspective, we highlight recent case studies illustrating the development of high-quality chemical probes for less-studied kinases and their application in target validation. We spotlight emerging techniques and approaches employed in the generation of chemical probes for protein kinases and beyond and discuss the associated challenges and opportunities.
MeSH term(s)	Animals ; Humans ; Molecular Probes/metabolism ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases/metabolism
Chemical Substances	Molecular Probes ; Protein Kinase Inhibitors ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2021-09-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c00980
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Article ; Online: The latest advances in the discovery of nitric oxide hybrid drug compounds.

Serafim, Ricardo A M / Pernichelle, Filipe G / Ferreira, Elizabeth I

Expert opinion on drug discovery

2017 Volume 12, Issue 9, Page(s) 941–953

Abstract: Introduction: There is a great interest in Nitric oxide (NO) within medicinal chemistry since it's involved in human signaling pathways. Prodrugs or hybrid compounds containing NO-donor scaffolds linked to an active compound are valuable, due to their ... ...

Abstract	Introduction: There is a great interest in Nitric oxide (NO) within medicinal chemistry since it's involved in human signaling pathways. Prodrugs or hybrid compounds containing NO-donor scaffolds linked to an active compound are valuable, due to their potential for modulating many pathological conditions due to NO's biological properties when released in addition to the native drug. Compounds that selectively inhibit nitric oxide synthase isoforms (NOS) can also increase therapeutic capacity, particularly in the treatment of chronic diseases. However, search for bioactive compounds to efficiently and selectively modulate NO is still a challenge in drug discovery. Areas covered: In this review, the authors highlight the recent advances in the strategies used to discover NO-hybrid derivatives, especially those related to anti-inflammatory, cardiovascular, anticancer and anti-microorganism activities. They also focus on: nitric oxide synthase inhibitors, NO delivery materials and other related activities. Expert opinion: The process of molecular hybridization can be used to obtain NO-releasing compounds that also interact with different targets. The main problem with this approach is to control NO multiple actions in the right biological system. However, the use of NO-releasing groups with many different scaffolds leads to new molecular structures for bioactive compounds, suggesting synergies.
MeSH term(s)	Animals ; Chemistry, Pharmaceutical/methods ; Drug Design ; Drug Discovery/methods ; Humans ; Nitric Oxide/metabolism ; Nitric Oxide Donors/pharmacology ; Nitric Oxide Synthase/antagonists & inhibitors ; Prodrugs ; Signal Transduction/drug effects
Chemical Substances	Nitric Oxide Donors ; Prodrugs ; Nitric Oxide (31C4KY9ESH) ; Nitric Oxide Synthase (EC 1.14.13.39)
Language	English
Publishing date	2017-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2259618-5
ISSN	1746-045X ; 1746-0441
ISSN (online)	1746-045X
ISSN	1746-0441
DOI	10.1080/17460441.2017.1344400
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Article: Discovery of a Potent and Highly Isoform-Selective Inhibitor of the Neglected Ribosomal Protein S6 Kinase Beta 2 (S6K2).

Gerstenecker, Stefan / Haarer, Lisa / Schröder, Martin / Kudolo, Mark / Schwalm, Martin P / Wydra, Valentin / Serafim, Ricardo A M / Chaikuad, Apirat / Knapp, Stefan / Laufer, Stefan / Gehringer, Matthias

Cancers

2021 Volume 13, Issue 20

Abstract: The ribosomal protein S6 kinase beta 2 (S6K2) is thought to play an important role in malignant cell proliferation, but is understudied compared to its closely related homolog S6 kinase beta 1 (S6K1). To better understand the biological function of S6K2, ...

Abstract	The ribosomal protein S6 kinase beta 2 (S6K2) is thought to play an important role in malignant cell proliferation, but is understudied compared to its closely related homolog S6 kinase beta 1 (S6K1). To better understand the biological function of S6K2, chemical probes are needed, but the high similarity between S6K2 and S6K1 makes it challenging to selectively address S6K2 with small molecules. We were able to design the first potent and highly isoform-specific S6K2 inhibitor from a known S6K1-selective inhibitor, which was merged with a covalent inhibitor engaging a cysteine located in the hinge region in the fibroblast growth factor receptor kinase (FGFR) 4 via a nucleophilic aromatic substitution (S
Language	English
Publishing date	2021-10-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13205133
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Article ; Online: Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold.

Serafim, Ricardo A M / Sorrell, Fiona J / Berger, Benedict-Tilman / Collins, Ross J / Vasconcelos, Stanley N S / Massirer, Katlin B / Knapp, Stefan / Bennett, James / Fedorov, Oleg / Patel, Hitesh / Zuercher, William J / Elkins, Jonathan M

Journal of medicinal chemistry

2021 Volume 64, Issue 18, Page(s) 13259–13278

Abstract: SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We ... ...

Abstract	SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Crystal structures of exemplar inhibitors bound to SLK and STK10 demonstrated the binding mode of the inhibitors and rationalized their selectivity. Cellular target engagement assays demonstrated the binding of the inhibitors to SLK and STK10 in cells. Further selectivity analyses, including analysis of activity of the reported inhibitors against off-targets in cells, identified compound
MeSH term(s)	Aniline Compounds/chemistry ; Aniline Compounds/metabolism ; Aniline Compounds/pharmacology ; Binding Sites ; Cell Line, Tumor ; Cell Movement/drug effects ; HEK293 Cells ; Humans ; Maleimides/chemistry ; Maleimides/metabolism ; Maleimides/pharmacology ; Microfilament Proteins/metabolism ; Molecular Docking Simulation ; Molecular Structure ; Phosphorylation/drug effects ; Protein Binding ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/chemistry ; Protein Serine-Threonine Kinases/metabolism ; Structure-Activity Relationship
Chemical Substances	Aniline Compounds ; Maleimides ; Microfilament Proteins ; Protein Kinase Inhibitors ; moesin (144131-77-1) ; SLK protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; STK10 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2021-08-31
Publishing country	United States
Document type	Journal Article ; 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.0c01579
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Article ; Online: Discovery of novel benzothiophene derivatives as potent and narrow spectrum inhibitors of DYRK1A and DYRK1B.

Segretti, Natanael D / Takarada, Jéssica E / Ferreira, Marcos A / da Silva Santiago, André / Teodoro, Bruno V M / Damião, Mariana C F C B / Godoi, Paulo H / Cunha, Micael R / Fala, Angela M / Ramos, Priscila Z / Ishikawa, Eloisa E / Mascarello, Alessandra / Serafim, Ricardo A M / Azevedo, Hatylas / Guimarães, Cristiano R W / Couñago, Rafael M

Bioorganic & medicinal chemistry letters

2022 Volume 68, Page(s) 128764

Abstract: The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B ... ...

Abstract	The discovery of potent and selective inhibitors for understudied kinases can provide relevant pharmacological tools to illuminate their biological functions. DYRK1A and DYRK1B are protein kinases linked to chronic human diseases. Current DYRK1A/DYRK1B inhibitors also antagonize the function of related protein kinases, such as CDC2-like kinases (CLK1, CLK2, CLK4) and DYRK2. Here, we reveal narrow spectrum dual inhibitors of DYRK1A and DYRK1B based on a benzothiophene scaffold. Compound optimization exploited structural differences in the ATP-binding sites of the DYRK1 kinases and resulted in the discovery of 3n, a potent and cell-permeable DYRK1A/DYRK1B inhibitor. This compound has a different scaffold and a narrower off-target profile compared to current DYRK1A/DYRK1B inhibitors. We expect the benzothiophene derivatives described here to aid establishing DYRK1A/DYRK1B cellular functions and their role in human pathologies.
MeSH term(s)	Humans ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Kinases ; Protein Serine-Threonine Kinases ; Protein-Tyrosine Kinases/metabolism ; Thiophenes
Chemical Substances	Protein Kinase Inhibitors ; Thiophenes ; benzothiophene (073790YQ2G) ; Protein Kinases (EC 2.7.-) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-05-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2022.128764
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Article ; Online: New antibacterial agents: Hybrid bioisoster derivatives as potential E. coli FabH inhibitors.

Segretti, Natanael D / Serafim, Ricardo A M / Segretti, Mariana C F / Miyata, Marcelo / Coelho, Fernando R / Augusto, Ohara / Ferreira, Elizabeth I

Bioorganic & medicinal chemistry letters

2016 Volume 26, Issue 16, Page(s) 3988–3993

Abstract: The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new ... ...

Abstract	The development of resistance to antibiotics by microorganisms is a major problem for the treatment of bacterial infections worldwide, and therefore, it is imperative to study new scaffolds that are potentially useful in the development of new antibiotics. In this regard, we propose the design, synthesis and biological evaluation of hybrid sulfonylhydrazone bioisosters/furoxans with potential antibacterial (Escherichia coli) activity. The most active compound of the series, (E)-3-methyl-4-((2-tosylhydrazono)methyl)-1,2,5-oxadiazole 2-oxide, with a MIC=0.36μM, was not cytotoxic when tested on Vero cells (IC50>100μM). To complement the in vitro screening, we also studied the interaction of the test compounds with β-ketoacyl acyl carrier protein synthase (FabH), the target for the parent compounds, and we observed three important hydrogen-bonding interactions with two important active site residues in the catalytic site of the enzyme, providing complementary evidence to support the target of the new hybrid molecules.
MeSH term(s)	Acetyltransferases/antagonists & inhibitors ; Acetyltransferases/metabolism ; Animals ; Anti-Bacterial Agents/chemical synthesis ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/toxicity ; Binding Sites ; Candida albicans/drug effects ; Catalytic Domain ; Cell Survival/drug effects ; Cercopithecus aethiops ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/toxicity ; Escherichia coli/drug effects ; Escherichia coli/enzymology ; Escherichia coli Proteins/antagonists & inhibitors ; Escherichia coli Proteins/metabolism ; Fatty Acid Synthase, Type II/antagonists & inhibitors ; Fatty Acid Synthase, Type II/metabolism ; Hydrogen Bonding ; Microbial Sensitivity Tests ; Molecular Docking Simulation ; Oxadiazoles/chemical synthesis ; Oxadiazoles/chemistry ; Oxadiazoles/toxicity ; Static Electricity ; Structure-Activity Relationship ; Vero Cells
Chemical Substances	1,2,5-oxadiazole 2-oxide ; Anti-Bacterial Agents ; Enzyme Inhibitors ; Escherichia coli Proteins ; Oxadiazoles ; Acetyltransferases (EC 2.3.1.-) ; fabH protein, E coli (EC 2.3.1.180) ; Fatty Acid Synthase, Type II (EC 6.-)
Language	English
Publishing date	2016--15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2016.06.089
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Article: Development of Pyridine-based Inhibitors for the Human Vaccinia-related Kinases 1 and 2.

Serafim, Ricardo A M / de Souza Gama, Fernando H / Dutra, Luiz A / Dos Reis, Caio V / Vasconcelos, Stanley N S / da Silva Santiago, André / Takarada, Jéssica E / Di Pillo, Fúlvia / Azevedo, Hatylas / Mascarello, Alessandra / Elkins, Jonathan M / Massirer, Katlin B / Gileadi, Opher / Guimarães, Cristiano R W / Couñago, Rafael M

ACS medicinal chemistry letters

2019 Volume 10, Issue 9, Page(s) 1266–1271

Abstract: Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their ... ...

Abstract	Vaccinia-related kinases 1 and 2 (VRK1 and VRK2) are human Ser/Thr protein kinases associated with increased cell division and neurological disorders. Nevertheless, the cellular functions of these proteins are not fully understood. Despite their therapeutic potential, there are no potent and specific inhibitors available for VRK1 or VRK2. We report here the discovery and elaboration of an aminopyridine scaffold as a basis for VRK1 and VRK2 inhibitors. The most potent compound for VRK1 (
Language	English
Publishing date	2019-08-19
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.9b00082
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