Background/Purpose: Spleen tyrosine kinase (SYK) is a potential target for treatment of several diseases including rheumatoid arthritis.  SYK is a member of the Zeta-chain-associated protein kinase 70 (ZAP70) family of non-receptor protein kinases, critical in signaling downstream of Fc epsilon receptor I (FceRI) in mast cells and basophils, B-cell receptor (BCR) in B cells, and the collagen receptor in platelets.  ZAP70, plays a predominant role in T-cell receptor (TCR) signaling in mature T cells.  Here, we report the in vitro, in vivo, and early clinical characterization of a highly selective and potent dual SYK/ZAP70 inhibitor, MK-8457. 

Methods: The in vitro characteristics of MK-8457 were evaluated in a series of biochemical and cellular assays.  The in vivo characteristics of MK-8457 were evaluated in the rat adjuvant- and collagen-induced arthritis models.  MK-8457 preclinical PK-PD-Efficacy relationship was established to select clinical doses required for efficacy in RA.  Healthy volunteer clinical studies assessed the PK, PD, and safety of MK-8457 in single- and multiple-rising dose studies. 

Results: MK-8457 is a potent, reversible ATP competitive inhibitor of SYK and ZAP70, displaying comparable cellular activity for these two kinases despite 40x enzymatic selectivity for SYK vs. ZAP70.  Beyond ZAP70, out of 191 off-target kinases tested, MK-8457 inhibits only 3 kinases (TRKC, SRC, BLK) with IC₅₀ values less than 100-fold above the SYK IC₅₀.  In vitro, MK-8457 is a potent inhibitor of (1) FceRI-mediated anti-IgE induced degranulation in primary human mast cells (38 ± 20 nM) and human whole blood basophils (797 ± 365 nM), (2) BCR-mediated anti-IgM induced pBLNK activation in human RAMOS cells (35 ± 27 nM) and anti-CD79b induced CD69 upregulation in human whole blood B cells (1398 ± 505 nM), and (3) TCR-mediated anti-CD3 induced IL-2 production in Jurkat cells (84 ± 26 nM) and human whole blood phytohemagglutinin induced IL-2 production (1175 ± 362 nM).  MK-8457 also inhibits collagen-induced platelet aggregation in human platelet rich plasma, with 20x reduced potency (19 ± 3 uM) as compared with the human whole blood basophil, B-cell, and T-cell assays.  MK-8457 produces dose-dependent inhibition of adjuvant- and collagen-induced arthritis, as assessed by changes in paw thickness.  Preclinical PK-PD-Efficacy modeling and simulations suggest that high level of SYK/ZAP70 inhibition (69%) is required to attain nearly full suppression of the CIA response.  In healthy volunteers, MK-8457 is rapidly absorbed, shows increased exposure with dose, with a terminal half-life estimated to be 10-20 hours.  MK-8457 was generally safe and well-tolerated in single dose up to 800 mg and multiple doses of 200 mg twice daily for up to 10 days.  There was evidence of increased bleeding times at the T_max in single dose studies; however, there were no bleeding adverse events.  The C_maxfor this effect in healthy volunteers is ~2x higher than observed at steady state for the highest dose (100 mg BID) tested in Phase II RA studies. 

Conclusion: These data suggest that MK-8457 has the appropriate characteristics for assessment of the hypothesis that a selective SYK/ZAP70 inhibitor is efficacious in RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-and-clinical-phase-i-profile-of-mk-8457-a-selective-spleen-tyrosine-kinase-and-zeta-chain-associated-protein-kinase-70-inhibitor-developed-for-the-treatment-of-rheumatoid-arthritis/