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

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(10), С. 7668 - 7758

Опубликована: Май 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.

Язык: Английский

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

MedComm – Oncology, Год журнала: 2023, Номер 2(4)

Опубликована: Окт. 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

Язык: Английский

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

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(12)

Опубликована: Янв. 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.

Язык: Английский

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Morita–Baylis–Hillman Adduct Chemistry as a Tool for the Design of Lysine-Targeted Covalent Ligands

ACS Medicinal Chemistry Letters, Год журнала: 2025, Номер 16(3), С. 397 - 405

Опубликована: Фев. 28, 2025

The use of Targeted Covalent Inhibitors (TCIs) is an expanding strategy for the development innovative drugs. It driven by two fundamental steps: (1) recognition target site molecule and (2) establishment covalent interaction its reactive group. new TCIs depends on warheads. Here, we propose Morita–Baylis–Hillman adducts (MBHAs) to covalently bind Lys strategically placed inside a lipophilic pocket. A human cellular retinoic acid binding protein II mutant (M2) was selected as test bench library 19 MBHAs. noncovalent step investigated molecular docking studies, while experimentally entire incubated with M2 crystallized confirm lysine. results, rationalized through analysis, support our hypothesis MBHAs scaffolds design lysine-TCIs.

Язык: Английский

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Lysine-Reactive N-Acyl-N-aryl Sulfonamide Warheads: Improved Reaction Properties and Application in the Covalent Inhibition of an Ibrutinib-Resistant BTK Mutant

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(48), С. 26202 - 26212

Опубликована: Ноя. 21, 2023

The covalent inhibition of a target protein has gained widespread attention in the field drug discovery. Most current drugs utilize high reactivity cysteines toward modest electrophiles. However, there is growing need for warheads that can lysine residues to expand range covalently druggable proteins and deal with emerging mutations resistant cysteine-targeted drugs. We have recently developed an N-acyl-N-alkyl sulfonamide (NASA) as lysine-targeted electrophile. Despite its successful application, this NASA warhead suffered from instability physiological environments, such serum-containing medium, because intrinsic reactivity. In study, we sought modify structure found N-acyl-N-aryl sulfonamides (ArNASAs) are promising electrophiles use strategy. prepared focused library ArNASA derivatives diverse structures identified several candidates suppressed hydrolysis-mediated inactivation reduced nonspecific reactions off-target proteins, without sacrificing target. These reaction properties enabled improved intracellular heat shock 90 (HSP90) presence serum development first irreversible inhibitor ibrutinib-resistant Bruton's tyrosine kinase (BTK) bearing C481S mutation. This study clearly demonstrated set create highly potent highlighted importance enriching arsenal lysine-reactive warheads.

Язык: Английский

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Aminomethyl Salicylaldehydes Lock onto a Surface Lysine by Forming an Extended Intramolecular Hydrogen Bond Network

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(35), С. 24233 - 24237

Опубликована: Авг. 23, 2024

The development of electrophilic ligands that rapidly modify specific lysine residues remains a major challenge. Salicylaldehyde-based inhibitors have been reported to form stable imine adducts with the catalytic protein kinases. However, targeted in these examples is buried hydrophobic environment. A key unanswered question whether this strategy can be applied on surface protein, where rapid hydrolysis resulting salicylaldimine more likely. Here, we describe series aminomethyl-substituted salicylaldehydes target fully solvated ATPase domain Hsp90. By systematically varying orientation salicylaldehyde, discovered long residence times, best which engages Hsp90 quasi-irreversible manner. Crystallographic analysis revealed daisy-chain network intramolecular hydrogen bonds locked into position by adjacent piperidine linker. This study highlights potential aminomethyl generate conformationally stabilized, hydrolysis-resistant imines, even when far from ligand binding site and exposed bulk solvent.

Язык: Английский

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Small Molecule-Induced Post-Translational Acetylation of Catalytic Lysine of Kinases in Mammalian Cells

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(34), С. 23978 - 23988

Опубликована: Авг. 20, 2024

Reversible lysine acetylation is an important post-translational modification (PTM). This process in cells typically carried out enzymatically by acetyltransferases and deacetylases. The catalytic the human kinome highly conserved ligandable. Small-molecule strategies that enable of on kinases a target-selective manner therefore provide tremendous potential kinase biology. Herein, we report first small molecule-induced chemical strategy capable global from mammalian cells. By surveying various lysine-acetylating agents installed promiscuous kinase-binding scaffold, Ac4 was identified shown to effectively acetylate >100 different protein live Jurkat/K562 In order demonstrate this reversible kinases, further developed six acetylating compounds basis VX-680 (a noncovalent inhibitor AURKA). Among them, Ac13/Ac14, while displaying excellent vitro potency sustained cellular activity against AURKA, showed robust its (K162) manner, leading irreversible inhibition endogenous activity. reversibility confirmed Ac14-treated recombinant AURKA protein, followed deacetylation with SIRT3 deacetylase). Finally, Ac13-induced demonstrated SIRT3-transfected HCT116 disclosing cell-active both our could useful tool biology drug discovery.

Язык: Английский

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Tying the knot with lysine

Nature Reviews Chemistry, Год журнала: 2024, Номер 8(4), С. 235 - 237

Опубликована: Март 18, 2024

Язык: Английский

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Lysine-Targeted Covalent Inhibitors of PI3Kδ Synthesis and Screening by In Situ Interaction Upgradation

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 19, 2024

Targeting the lysine residue of protein kinases to develop covalent inhibitors is an emerging hotspot. Herein, we have reported approach lysine-targeted PI3Kδ by in situ interaction upgradation H-bonding bonding. Several warhead groups were introduced and screened situ, leading bearing aromatic esters with high bioactivity selectivity. Compound A11 phenolic ester was finally optimized show a long duration action SU-DHL-6 cells multiple assays. Docking simulation further mass spectrometry confirmed that bound covalent-bonding interactions Lys779. Furthermore, exhibited potently antitumor efficacy without obvious toxicity Pfeiffer xenograft mouse models. This study identified be much more effective agent vitro vivo as inhibitor, it also provided practical for development inhibitors.

Язык: Английский

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O-Cyanobenzaldehydes Irreversibly Modify Both Buried and Exposed Lysine Residues in Live Cells

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Март 27, 2025

Lysine residue represents an attractive site for covalent drug development due to its high abundance (5.6%) and critical functions. However, very few lysines have been characterized be accessible ligands perturb the protein functions, owing their protonation state adjacent steric hindrance. Herein, we report a new lysine bioconjugation chemistry, O-cyanobenzaldehyde (CNBA), that enables selective modification of ε-amine form iso-indolinones under physiological conditions. Activity-based proteome profiling enabled mapping 3451 residues 85 endogenous kinases in live cells, highlighting potential modifying hyper-reactive within or buried catalytic kinome. Further crystallography mass spectrometry confirmed K271_ABL1 K162_AURKA are covalently targetable sites kinases. Leveraging structure-based design, incorporated CNBA into core structure Nutlin-3 irreversibly inhibit MDM2-p53 interaction by targeting exposed K94 on surface murine double minute 2. Importantly, demonstrated application as lysine-recognized agent developing antibody-drug conjugates. The results collectively validate efficient with broad applications both cells.

Язык: Английский

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