Background/Purpose: Bruton’s tyrosine kinase (BTK) is an important component of B cell and Fc receptor signaling and has been shown to be critical for B-cell proliferation and differentiation.  Expression of BTK in cell types that are dysregulated or which play a pathological role in arthritis suggests that inhibition of BTK may be therapeutically advantageous in the treatment of rheumatoid arthritis.  For use in chronic disease settings such as arthritis highly specific inhibitors are desired.  However, the ATP binding site of kinases is highly conserved and it is often difficult to design competitive inhibitors exhibiting a high degree of selectivity.  One approach taken by our group and others to develop highly specific BTK inhibitors is to target a cysteine residue immediately outside the ATP binding pocket.  Unfortunately, the position of this cysteine is conserved in 11 kinases within the human kinome including, for example, EGFR.  Consequently many BTK inhibitors also inhibit those cysteine-containing kinases.

Methods: A novel and selective BTK inhibitor was identified using in vitro kinase assays.  The compound was further characterized using in vitro ADME assays and cellular assays.  In vivo efficacy was monitored using the collagen-induced arthritis model in B10 mice.

Results: We report here the characterization of AEG42766, a highly potent and selective BTK inhibitor with an apparent IC50 of 8nM against purified BTK and no significant activity against EGFR. AEG42766 inhibits IgM-mediated proliferation of murine splenocytes and purified human B cells with EC50s of 0.8nM and 0.4nM, respectively. AEG42766 shows good stability in human liver microsomes. In vivo PO administration in mice indicates oral bioavailability of >25% and results in robust, long duration inhibition of BTK. Consistent with profound inhibition of BTK, in vivo pharmacology studies demonstrate that AEG42766 is active in models of reverse passive anaphylaxis and collagen-induced arthritis.

Conclusion: AEG42766 is a highly potent BTK inhibitor suitable for further development as a candidate to treat rheumatoid arthritis and other diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pre-clinical-development-of-a-novel-potent-and-selective-btk-inhibitor-for-autoimmune-disease-and-inflammation-including-arthritis/