Kinase inhibition in autoimmunity and inflammation

Abstract

Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches to alleviate dysregulated inflammation has been to target the activity of kinases that regulate production of inflammatory mediators. Small-molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics. However, designing kinase inhibitors with target selectivity and minimal off-target effects can be challenging. Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug-like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2. This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways.

Druggable Transient Pockets in Protein Kinases

“…However, the U.S. Food and Drug Administration–approved inhibitors only target approximately 20 protein kinases in the human kinome [ 4 , 8 ]. Thus, the human kinome is still an attractive drug target with a significant research scope [ 4 , 10 ].…”

Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment

“…Abbreviations: cGAS: cGMP-AMP synthase; CIITA: class II, major histocompatibility complex, transactivator; IRF: interferon regulatory factor; MDA5: melanoma differentiation-associated protein 5; MAVS: mitochondrial antiviral signaling protein; MyD88: myeloma differentiation primary response 88; NLRs: nucleotide-binding oligomerization domain-like receptors; NLRP: nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing (also abbreviated as NALP); NOD: nucleotide oligomerization domain; RIG-1: retinoic acid inducible gene-1; STING: stimulator of interferon genes; TLR: toll-like receptor; TRIF: TIR-domain-containing adapter-inducing IFN-beta. Primary data from (Zhao et al, 2015;Zarrin et al, 2020).…”

Involvement of Interleukin-1 Receptor-Associated Kinase 4 and Interferon Regulatory Factor 5 in the Immunopathogenesis of SARS-CoV-2 Infection: Implications for the Treatment of COVID-19

“…IRAK4, recruited with other binding partners to MYD88 (Figure 1) forms the myddosome (14)(15)(16), which is activated by ligands of the IL-1 receptor or TLRs that bind MYD88 (13,17,18). IRAK4 is recruited to the complex with IRAK1 and TRAF6 (19).…”