Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets
Abstract
:1. Introduction
2. Recent Studies on Covalent Inhibitors
2.1. Conventional Covalent Inhibitors
Name/Structure | Target(s) | Therapeutic Indication | Warhead | Ref. (Approval Date) |
---|---|---|---|---|
Boceprevir | Viral protease (HCV NS3) | Antiviral (hepatitis) | α-Ketoamide | (13 May 2011) |
Nirmatrelvir (1) | Viral protease (SARS-CoV-2 Mpro) | Antiviral (COVID-19) | Nitrile | [2] (Emergency use authorization, 22 December 2021) |
ETX0462 (2) | Bacterial protease (PBP3, β-lactamase) | Antibiotic (MDR infection) | Diazabicyclooctane | [29] |
Cefiderocol | Bacterial protease (PBP) | Antibiotic (MDR infection) | β-Lactam | (14 November 2019) |
Vaborbactam | Bacterial protease (β-lactamase) | Antibiotic (MDR infection) | Cyclic boronic acid | (29 August 2017) |
Relebactam | Bacteiral protease (β-lactamase) | Antibiotic (MDR infection) | Diazabicyclooctane | (16 July 2019) |
Bortezomib | Human proteasome | Anticancer (leukemia) | Boronic acid | (13 May 2003) |
Carfilzomib | Human proteasome | Anticancer (multiple myeloma) | Epoxy ketone | (20 July 2012) |
Ixazomib | Human proteasome | Anticancer (multiple myeloma) | Bornoic acid | (20 November 2015) |
FT827 (3) | Deubiquitinase (USP7) | Anticancer | Vinyl sulfonamide | [30] |
XL177A | Deubiquitinase (USP7) | Anticancer | Chlorotetrahydroacridine | [31] |
Wortmannin | Kinase (PI3K) | N/A | Furan | [1] |
A5 (4) | Kinase (BCR-ABL) | Anticancer (chronic myeloid leukemia) | Aldehyde | [13] |
2.2. Targeted Covalent Inhibitors
Name/Structure | Target(s) | Therapeutic Indication | Warhead | Ref. (Approval Date) |
---|---|---|---|---|
Acalabrutinib | Kinase (BTK) | Anticancer (mantle cell lymphoma) | 2-Butyneamide | (31 October 2017) |
Zanubrutinib | Kinase (BTK) | Anticancer (mantle cell lymphoma) | Acrylamide | (14 November 2019) |
Afatinib | Kinase (EGFR T790M and pan-HER) | Anticancer (NSCLC) | Acrylamide | (12 July 2013) |
Neratinib | Kinase (pan-HER) | Anticancer (breast cancer) | Acrylamide | (17 July 2017) |
Dacomitinib | Kinase (pan-HER) | Anticancer (NSCLC) | Acrylamide | (27 September 2018) |
Mobocertinib (5) | Kinase (EGFR ex20ins) | Anticancer (NSCLC) | Acrylamide | [41] (15 September 2021) |
Lazertinib | Kinase (EGFR) | Anticancer (NSCLC) | Acrylamide | [42] (Accerlated approval, 21 May 2021, combination with amivantamab) |
Nazartinib | Kinase (EGFR) | Anticancer (NSCLC) | Acrylamide | [42] |
Sotorasib (6) | GTPase (KRASG12C) | Anticancer (NSCLC) | Acrylamide | [14,43,44,45,46] (28 May 2021) |
Adagrasib | GTPase (KRASG12C) | Anticancer (NSCLC) | 2-Fluoroacrylamide | [47] (Under new drug application) |
G12Si-5 (7) | GTPase (KRASG12S) | Anticancer (NSCLC) | β-Lactam | [48] |
G12R inhibitor-4 (8) | GTPase (KRASG12R) | Anticancer (NSCLC) | α,β-Diketoamide | [49] |
2.3. Expanded Targeted Covalent Inhibitors
Name/Structure | Target(s) | Therapeutic Indication | Warhead | Ref. (Approval Date) |
---|---|---|---|---|
Selinexor (9) | Protein–protein interaction (XPO1 and NES) | Anticancer | Acrylamide | [16] (3 July 2019) |
DC-LC3in-D5 (10) | Protein–protein interaction (LC3B and LIR) | N/A | Enaminones | [17] |
Covalent Nutlin-3 (11) | Protein–protein interaction (HDM2and p53) | Anticancer | N-Acyl-N-alkyl sulfonamides | [18] |
TED-347 (12) | Protein–protein interaction (Yap1 and TEAD4) | Anticancer | Chloromethyl ketone | [19] |
C-178 | Membrane protein (mouse STING) | Anti-inflammatory drugs (autoimmune disease) | Nitrofuran | [55] |
A3AR inhibitor 17b | Membrane protein (GPCR hA3AR) | Glaucoma, Asthma | Fluorosulfonyl | [56] |
α-galactosylceramides | Membrane protein (CD1d) | Anti-inflammatory drugs | Chloroacetamide | [57] |
SB1453 | Transcription factor (PPARγ) | Anti-diabetic (type II diabetes) | 2-chloro-5-nitrobenzamide | [58] |
BPK-26 | Transcription factor (NR0B1) | Anticancer | 2-Chloroacetamide | [59] |
Voxelotor | Sickle cell hemoglobin | Sickle cell disease | Aldehyde | [60] (25 November 2019) |
3. Summary and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Lee, J.; Park, S.B. Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets. Pharmaceuticals 2022, 15, 1478. https://doi.org/10.3390/ph15121478
Lee J, Park SB. Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets. Pharmaceuticals. 2022; 15(12):1478. https://doi.org/10.3390/ph15121478
Chicago/Turabian StyleLee, Jesang, and Seung Bum Park. 2022. "Extended Applications of Small-Molecule Covalent Inhibitors toward Novel Therapeutic Targets" Pharmaceuticals 15, no. 12: 1478. https://doi.org/10.3390/ph15121478