Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases
Abstract
:1. Introduction
2. BTK as a Biological Target for Drug Development
2.1. BTK Structure and Biological Functions
2.2. Analysis of Ligand–Protein Interactions between BTK and Representative Inhibitors
3. Current Development of BTK Inhibitors for the Treatment of Autoimmune and Inflammatory Diseases
3.1. Covalent Irreversible Inhibitors
3.1.1. Fused Bicyclic Heterocycle (Pyrazolopyrimidine, Pyrrolopyrimidine, Imidazopyrazine, Purinone, Imidazolonepyridine, Pyrazolopyridazinone, Thienopyrimidine, Furopyrimidine, and Indole)
3.1.2. Monoheterocycle (Aminopyrimidine, Pyridinecarboxamide and Pyrazolecarboxamide)
3.1.3. Fused Tricyclic Heterocycle (Imidazoquinoxaline)
3.2. Covalent Reversible Inhibitors
3.3. Non-Covalent Reversible Inhibitors
3.3.1. Fused Bicyclic Heterocycle (Imidazopyrazine, Pyrrolopyrimidine, Cinnoline and Quinoline)
3.3.2. Monoheterocycle (Aminopyrazinone, Aminopyridazinone, Aminopyridinone, Aminopyrimidine, and Amino-1,3,5-triazine)
3.3.3. Fused Tricyclic Heterocycle
4. Summary of Structural Information in the Ligand-Binding Site of BTK
5. Conclusions and Outlooks
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AIA | Adjuvant-Induced Arthritis |
BCR | B-cell receptor |
BTK | Bruton’s tyrosine kinase |
cGVHD | Chronic graft versus host disease |
CAIA | Collagen antibody-induced arthritis |
CIA | Collagen-induced arthritis |
CLL | Chronic lymphocytic leukemia |
COVID-19 | Coronavirus Disease 19 |
DAMA | Damage-associated molecular patterns |
EAE | Experimental autoimmune encephalomyelitis |
EGFR | Epidermal growth factor receptor |
hPBMC | Human Peripheral Blood Mononuclear Cell |
hWB | Human whole blood |
IC | Immune complexes |
MCL | Mantle cell lymphoma |
MS | Multiple sclerosis |
RRMS | Relapsing–Remitting Multiple Sclerosis |
NTN | Nephrotoxic nephritis |
NSCL | Non-Small Cell Lung Cancer |
PAMA | Pathogen-associated molecular patterns |
PCA | Passive cutaneous anaphylaxis |
PD | Pharmacodynamics |
PH | Pleckstrin homology domain |
PK | Pharmacokinetics |
RA | Rheumatoid arthritis |
RMS | Relapsing multiple sclerosis |
SAR | Structure–activity relationship |
SH2/SH3 | Src homology 2/3 domain |
SLE | Systemic lupus erythematosus |
SLL | Small lymphocytic lymphoma |
SYK | Spleen tyrosine kinase |
TCIs | Targeted covalent inhibitors |
TH | Tec homology domain |
TK | Tyrosine kinase domain |
TLRs | Toll-like receptors |
WM | Waldenström’s macroglobulinemia |
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Compound Number and Common Name | Trade Name | Indications | Dosage | Corporation | Stages |
---|---|---|---|---|---|
1 (Ibrutinib) | Imbruvia | MCL, CLL, SLL, WM, cGVHD, etc | 420 or 560 mg/day, capsule or tablet | Pharmacyclics/Johnson | Approved (FDA: November 2013; EMA: 2014.4; JP PMDA: March 2016) |
5 (Zanubrutinib) [4] | Brukinsa | MCL | 80 mg bid, capsule | BeiGene | Approved (FDA: November 2019; CN NMPA: June 2020) |
7 (Acalabrutinib) | Calquence | MCL, CLL, SLL | 100 mg bid, capsule | Acerta Pharma | Approved (FDA: November 2017) |
8 (Tirabrutinib/ONO/GS-4059) | Velexbru | PCNSL | 480 mg qd, tablet | Ono Pharma | Approved (JP PMDA: 25 March 2020) |
11 (Olmutinib/HM-61713/BI-1482694) | Olita | NSCLC | 800 mg/day, tablet | Hanmi Pharmaceuticals | Approved (Korea: May 2016) |
19 (Orelabrutinib/ICP-022) | MCL, CLL, SLL | 150 mg qd, tablet | InnoCare Pharma | Approved (CN NMPA: December 2020) |
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Zhang, D.; Gong, H.; Meng, F. Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases. Molecules 2021, 26, 4907. https://doi.org/10.3390/molecules26164907
Zhang D, Gong H, Meng F. Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases. Molecules. 2021; 26(16):4907. https://doi.org/10.3390/molecules26164907
Chicago/Turabian StyleZhang, Datong, He Gong, and Fancui Meng. 2021. "Recent Advances in BTK Inhibitors for the Treatment of Inflammatory and Autoimmune Diseases" Molecules 26, no. 16: 4907. https://doi.org/10.3390/molecules26164907