Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(14), P. 9297 - 9312

Published: July 5, 2023

Within druggable target space, new small-molecule modalities, particularly covalent inhibitors and targeted degraders, have expanded the repertoire of medicinal chemists. Molecules with such modes action a large potential not only as drugs but also chemical probes. Criteria previously been established to describe potency, selectivity, properties probes that are qualified enable interrogation validation drug targets. These definitions tailored reversibly acting modulators fall short in their applicability other modalities. While initial guidelines proposed, we delineate here full set criteria for characterization covalent, irreversible well heterobifunctional degraders ("proteolysis-targeting chimeras", or PROTACs) molecular glue degraders. We propose modified potency selectivity compared those reversible inhibitors. discuss relevance highlight examples suitable probe pathfinder compounds.

Language: Английский

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Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758

Published: May 7, 2024

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.

Language: Английский

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2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(7), P. 3844 - 3849

Published: Feb. 12, 2023

Lysine-targeting irreversible covalent inhibitors have attracted growing interests in recent years, especially the fields of kinase research. Despite encouraging progress, few chemistries are available to develop that exclusively lysine-targeting, selective, and cell-active. We report herein a 2-ethynylbenzaldehyde (EBA)-based, lysine-targeting strategy generate potent selective small-molecule ABL by selectively targeting conserved catalytic lysine enzyme. showed resulting compounds were cell-active, capable covalently engaging endogenous K562 cells with long-residence time off-targets. further validated generality this developing EBA-based against EGFR (a kinase) Mcl-1 nonkinase) reacted noncatalytic within each target.

Language: Английский

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Small-molecule probes from bench to bedside: advancing molecular analysis of drug–target interactions toward precision medicine

Chemical Society Reviews, Journal Year: 2023, Volume and Issue: 52(16), P. 5706 - 5743

Published: Jan. 1, 2023

Integrated development of designer chemical tools and complementary analytical technologies empowers new scientific clinical opportunities.

Language: Английский

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Development of covalent inhibitors: Principle, design, and application in cancer

MedComm – Oncology, Journal Year: 2023, Volume and Issue: 2(4)

Published: Oct. 31, 2023

Abstract Covalent inhibitors have been a rapidly growing field in drug discovery due to their therapeutic potential and unique advantages cancer therapy. As opposed noncovalent inhibitory drugs, covalent reversibly or irreversibly modify proximal nucleophilic amino acid residues on proteins, aiming selectively recognize bind protein targets addressing some of the challenges faced by drugs. Most successful targeted depend primarily binding‐site cysteine residues, but this has limitations for certain that lack targetable residues. Recently, rational design probes targeting other such as lysine, tyrosine, serine, turned out be another promising strategy Thus, development novel strategies extend scope binding improve properties is required. This review gives summary noncysteine from different aspects, including target identification, structure–activity relationships, strategies, properties, hope providing scientific reference future means expanding research

Language: Английский

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Global Reactivity Profiling of the Catalytic Lysine in Human Kinome for Covalent Inhibitor Development

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(12)

Published: Jan. 22, 2024

Abstract Advances in targeted covalent inhibitors (TCIs) have been made by using lysine‐reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell‐active TCIs are however available. We report herein activity‐based probes (ABPs; 2–14 ) based on chemistry aryl fluorosulfates (ArOSO 2 F) capable global reactivity profiling catalytic lysine human kinome from mammalian cells. concurrently developed reversible ABPs ( 15 / 16 installing salicylaldehydes (SA) onto a promiscuous kinase‐binding scaffold. The stability and amine these exhibited broad range tunability. X‐ray crystallography mass spectrometry (MS) confirmed successful engagement between ArOSO F 9 SRC kinase. Chemoproteomic studies enabled >300 endogenous kinases, thus providing landscape ligandable lysines kinome. By further introducing into VX‐680 (a noncovalent inhibitor AURKA kinase), we generated novel that excellent vitro potency reasonable cellular activities with prolonged residence time. Our work serves as general guide F‐based TCIs.

Language: Английский

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Applications of covalent chemistry in targeted protein degradation

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(22), P. 9243 - 9261

Published: Jan. 1, 2022

This review summarizes the recent work of covalent chemistry in targeted protein degradation and describes concept, pros cons, development, outlook PROTACs.

Language: Английский

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The expanding repertoire of covalent warheads for drug discovery

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103799 - 103799

Published: Oct. 13, 2023

Language: Английский

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How many kinases are druggable? A review of our current understanding

Biochemical Journal, Journal Year: 2023, Volume and Issue: 480(16), P. 1331 - 1363

Published: Aug. 29, 2023

There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible discover a drug each individual kinase? For every kinase, we gathered data on their citation count, availability of chemical probes, approved investigational drugs, PDB structures, biochemical cellular assays. Analysis these factors highlights which kinase groups have wealth information available, still room progress. The suggest disproportionate focus the more well characterized while much kinome remains comparatively understudied. It noteworthy that tool compounds understudied already been developed, there untapped potential further development this space. Finally, review discusses different strategies employed generate selectivity between kinases. Given large volume available progress made past 20 years when comes drugging kinases, believe develop compound kinase. We hope will prove be both useful resource as inspire discovery

Language: Английский

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Catalyst-free late-stage functionalization to assemble α-acyloxyenamide electrophiles for selectively profiling conserved lysine residues

Communications Chemistry, Journal Year: 2024, Volume and Issue: 7(1)

Published: Feb. 14, 2024

Abstract Covalent probes coupled with chemical proteomics represent a powerful method for investigating small molecule and protein interactions. However, the creation of reactive warhead within various ligands to form covalent has been major obstacle. Herein, we report convenient robust process assemble unique electrophile, an α- acyloxyenamide, through one-step late-stage coupling reaction. This procedure demonstrates remarkable tolerance towards other functional groups facilitates ligand-directed labeling in proteins interest. The group successfully incorporated into clinical drug targeting EGFR L858R mutant, erlotinib, pan-kinase inhibitor. resulting have shown be able covalently engage lysine residue proximal ATP-binding pocket mutant. A series active sites, Mg 2+ , sites kinases, such as K33 CDK1, CDK2, CDK5 were detected. is first engaging these conserved catalytic residues kinases inhibition. Further application this methodology natural products demonstrated its success profiling ligandable whole proteome. These findings offer insights development new targeted inhibitors (TCIs).

Language: Английский

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