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

Huan Ling,

Lin Li, Liping Duan

et al.

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: March 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.

Language: Английский

Reversible lysine-targeted probes reveal residence time-based kinase selectivity DOI
Tangpo Yang, Adolfo Cuesta, Xiaobo Wan

et al.

Nature Chemical Biology, Journal Year: 2022, Volume and Issue: 18(9), P. 934 - 941

Published: May 19, 2022

Language: Английский

Citations

76
Lysine-Targeting Reversible Covalent Inhibitors with Long Residence Time DOI
Rahi M. Reja, Wenjian Wang,

Yuhan Lyu

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(3), P. 1152 - 1157

Published: Jan. 18, 2022

We report a new reversible lysine conjugation that features novel diazaborine product and much slowed dissociation kinetics in comparison to the previously known iminoboronate chemistry. Incorporating diazaborine-forming warhead RMR1 peptide ligand gives potent long-acting covalent inhibitors of staphylococcal sortase. The efficacy sortase inhibition is demonstrated via biochemical cell-based assays. A comparative study an iminoboronate-forming highlights significance potential modulating bond achieving inhibitors.

Language: Английский

Citations

74
Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update DOI

Laura Hillebrand,

Xiaojun Julia Liang,

Ricardo A. M. Serafim

et al.

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

Citations

53
An update on the discovery and development of reversible covalent inhibitors DOI Open Access

Faridoon Faridoon,

Raymond Ng, Guiping Zhang

et al.

Medicinal Chemistry Research, Journal Year: 2023, Volume and Issue: 32(6), P. 1039 - 1062

Published: April 29, 2023

Language: Английский

Citations

46
Covalent Warheads Targeting Cysteine Residue: The Promising Approach in Drug Development DOI Creative Commons

Fangjiao Huang,

Xiaoli Han,

Xiaohui Xiao

et al.

Molecules, Journal Year: 2022, Volume and Issue: 27(22), P. 7728 - 7728

Published: Nov. 10, 2022

Cysteine is one of the least abundant amino acids in proteins many organisms, which plays a crucial role catalysis, signal transduction, and redox regulation gene expression. The thiol group cysteine possesses ability to perform nucleophilic redox-active functions that are not feasible for other natural acids. most common covalent acid residue has been shown react with variety warheads, especially Michael receptors. These unique properties have led widespread interest this nucleophile, leading development cysteine-targeting warheads different chemical compositions. Herein, we summarized various targeting their application drug development.

Language: Английский

Citations

60
Lysine-Targeted Reversible Covalent Ligand Discovery for Proteins via Phage Display DOI
Mengmeng Zheng, Fa‐Jie Chen, Kaicheng Li

et al.

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(34), P. 15885 - 15893

Published: Aug. 17, 2022

Binding via reversible covalent bond formation presents a novel and powerful mechanism to enhance the potency of synthetic inhibitors for therapeutically important proteins. Work on this front has yielded anticancer drug bortezomib as well antisickling voxelotor. However, rational design remains difficult even when noncovalent are available scaffold. Herein, we report chemically modified phage libraries, both linear cyclic, that incorporate 2-acetylphenylboronic acid (APBA) warhead bind lysines iminoboronate formation. To demonstrate their utility, these APBA-presenting libraries were screened against sortase A Staphylococcus aureus, spike protein SARS-CoV-2. For targets, peptide ligands readily identified with single-digit micromolar excellent specificity, enabling live-cell inhibition highly sensitive detection, respectively. Furthermore, our structure-activity studies unambiguously benefit APBA binding. Overall, contribution shows first time can be developed display interest. The platform should widely applicable proteins including those involved in protein-protein interactions.

Language: Английский

Citations

51
Cell‐Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR‐ABL Kinase DOI
Peng Chen, Jie Sun, Chengjun Zhu

et al.

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(26)

Published: April 19, 2022

Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a develop cell-active inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. validated strategy successfully (irreversible reversible) against BCR-ABL kinase. Our lead compounds showed high levels selectivity biochemical assays, exhibited nanomolar potency endogenous ABL kinase cellular were active most drug-resistant mutations. Among them, salicylaldehyde-containing A5 first-ever reversible inhibitor that possessed time-dependent inhibition with prolonged residence time few off-targets K562 cells. Bioinformatics further suggested generality our human kinome.

Language: Английский

Citations

49
2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases DOI
Peng Chen, Guanghui Tang, Chengjun Zhu

et al.

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

Citations

32
Small-molecule probes from bench to bedside: advancing molecular analysis of drug–target interactions toward precision medicine DOI
Sijun Pan, Aixiang Ding, Yisi Li

et al.

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

Citations

32
Development of covalent inhibitors: Principle, design, and application in cancer DOI Creative Commons
Lang Zheng, Yang Li,

Defa Wu

et al.

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

Citations

26