Nanoparticle-delivered siRNA targeting Bruton's tyrosine kinase for rheumatoid arthritis therapy

2019 ◽  
Vol 7 (11) ◽  
pp. 4698-4707 ◽  
Author(s):  
Gui Zhao ◽  
An Liu ◽  
Yue Zhang ◽  
Zu-Qi Zuo ◽  
Zhi-Ting Cao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tyrosine Kinase ◽  
Polymeric Nanoparticles ◽  
Cationic Lipid ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase

Treatment of rheumatoid arthritis (RA) with cationic lipid-assisted polymeric nanoparticles (CLANs) carrying siRNA targeting Bruton's tyrosine kinase (BTK).

scholarly journals DESIGN AND SYNTHESIS OF SOME NEWER IMIDAZOLYL HETEROCYCLES AS POTENT BTK INHIBITORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

2017 ◽  
Vol 9 (3) ◽  
pp. 80
Author(s):  
R. Priyadarsini ◽  
Anandhan Menaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Hydrogen Bond ◽  
Molecular Docking ◽  
Tyrosine Kinase ◽  
Pharmacophore Model ◽  
Spectral Studies ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Hydrogen Bond Acceptor ◽  
Btk Inhibitors

Objective: The rheumatoid arthritis as a global health problem over the past few decades, Emphasizes the need for discovery of new therapeutic disease modifying anti-rheumatoid Arthritis drugs (DMARD’s). Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor, tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in the development, differentiation and proliferation of B-lineage cells, thus making BTK an efficient therapeutic target for the treatment of rheumatoid arthritis. This prompted us to synthesise a novel series of Imidazolyl Heterocycles as potent BTK (Bruton’s Tyrosine Kinase) inhibitors with alleged Anti-Rheumatoid Arthritis properties. Methods: Newer BTK inhibitors containing one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) and three hydrophobic features based on that pharmacophore model for BTK were designed. The designed compounds were sorted by applying ADMET properties, Lipinski rule of five, molecular docking and Novelty prediction to refine the designed ligands. Finally, different five compounds containing Imidazole as the heterocyclic nucleus have been synthesized and characterized by different analytical methods like Chromatographic data, Elemental analysis and Spectral studies by IR, 1H NMR, 13C NMR, GC-MS. Molecular docking studies were performed against BTK using GLIDE 10.2. Results: Several important hydrogen bonds with BTK were revealed, which include the gatekeeper residue Glu475 and Met477 at the hinge region. Conclusion: Overall, this study suggests that the proposed ligands are found to be more effective BTK inhibitor as Anti-Rheumatoid arthritis agents.

Safety and Efficacy of Poseltinib, Bruton’s Tyrosine Kinase-Inhibitor, in Patients With Rheumatoid Arthritis: A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase-2 Study

2020 ◽  
pp. jrheum.200893
Author(s):  
Mark Genovese ◽  
Alberto Spindler ◽  
Akira Sagawa ◽  
Won Park ◽  
Anna Dudek ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Bruton’S Tyrosine Kinase ◽  
Phase 2 ◽  
Serious Adverse Events ◽  
Bruton's Tyrosine Kinase ◽  
Acr20 Response ◽  
Once Daily ◽  
Significant Difference

Objective To evaluate efficacy and safety of poseltinib (formerly LY3337641/HM71224), an irreversible covalent inhibitor of Bruton’s tyrosine kinase from a 2-part, Phase-2 trial (RAjuvenate) in adults with active rheumatoid arthritis (RA). Methods In Part A, 36 patients with mildly active RA were randomized 1:1:1:1 to oral poseltinib 5-, 10-, or 30-mg or placebo once-daily for 4 weeks to assess safety/tolerability. No safety signals precluded moving to Part B where 250 patients with moderate-to-severe RA were randomized 1:1:1:1 to oral poseltinib 5- (N=63), 10- (N=62), or 30-mg (N=63) or placebo (N=62) once-daily for 12 weeks. Parts A and B permitted stable doses of background disease-modifying antirheumatic drugs. The primary endpoint in Part B was proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 12. Logistic regression compared each poseltinib dose to placebo for primary/secondary endpoints. Nonresponder imputation was used for missing data. Results After interim analysis showed low likelihood of demonstrating significant efficacy, the sponsor discontinued Part B of the study. 189 (76%) patients completed 12 weeks in Part B; 61 discontinued study treatment (27 [44%] due to study termination by sponsor). There was no statistically significant difference in ACR20 response between any dose of poseltinib and placebo at Week 12 (p<0.05 for all comparisons). Five serious adverse events occurred (n=2, placebo; n=3, 30-mg); there was 1 death due to a fall. Conclusion While no safety findings precluded continuation, the study was terminated after interim data demonstrated low likelihood of benefit in RA.

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