Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Spleen tyrosine kinase (SYK) is a key mediator of signaling events downstream of a wide array of receptors important for immune function, including the B cell antigen receptor, immunoglobulin receptors bearing the Fcg or Fce chain, and other ITAM-containing C-type lectin and integrin receptors. Therefore, Syk inhibition has attracted considerable interest for treatment of autoimmune and allergic diseases. In this report, we present a highly potent and selective, orally available Syk inhibitor and its efficacies in rodent models of rheumatoid arthritis.
Methods:
Utilizing a series in vitro biochemical and cellular assays and in vivo pharmacological models of rheumatoid arthritis, Syk inhibitors were designed and evaluated to identify a drug candidate with excellent potency, selectivity, and drug-like properties.
Results:
HM-0523 demonstrated high potency against Syk enzyme activity (IC50=20 nM) in vitro. The compound also exhibited its high kinome selectivity, although it cross-inhibited several kinases such as Flt3 with IC50=63 nM. HM-0523 also displayed functional activities in multiple cellular assays in various human cell types. It blocked FceR crosslinking-induced degranulation in mast cells (IC50=30 nM), FceR engagement-mediated TNF-a and IL-6 production in BMMC (IC50=52 and 78 nM, respectively), FcgR engagement-mediated TNF-a production in monocytes (IC50=54 nM). In human whole blood, HM-0523 potently inhibited BCR mediated B cell activation (IC50=120 nM) and FcεR1 mediated basophil degranulation (IC50=145 nM). HM-0523 was further evaluated in the models of rheumatoid arthritis. In mice collagen-induced arthritis model, treatment with HM-0523 after disease onset significantly reduced disease severity in a dose dependent manner with estimated ED50=4~5 mg/kg QD. Consistent with its efficacy in mice, HM-0523 also suppressed paw swelling with ED50=1.4 mg/kg QD in rat collagen-induced arthritis model. Furthermore, HM-0523 inhibited synovial proinflammatory cytokine production and inflammatory markers in the blood, suggesting its mechanism of action correlated with its clinical benefits in those models of rheumatoid arthritis. In addition, HM-0523 has demonstrated its superior in vitro potency, selectivity,in vivo efficacy and PK profile in preclinical animal models to current clinical lead fostamatinib that is under evaluation in Phase III clinical trials for Rheumatoid Arthritis.
Conclusion:
Our data demonstrated that HM-0523, acting through selective inhibition of Syk activation, exhibited significantly beneficial effects in rodent models of rheumatoid arthritis. These results strongly support further development of HM-0523 as a promising new agent for the treatment of rheumatoid arthritis.
Disclosure:
Y. Cai,
Hutchison Medipharma Limited,
3;
Z. C. Sun,
Hutchison Medipharma Limited,
3;
P. Ren,
Hutchison Medipharma Limited,
3;
L. Fang,
Hutchison Medipharma Limited,
3;
X. Dai,
Hutchison Medipharma Limited,
3;
Z. Wu,
Hutchison Medipharma Limited,
3;
Q. Dong,
Hutchison Medipharma Limited,
3;
X. Wang,
Hutchison Medipharma Limited,
3;
J. Wang,
Hutchison Medipharma Limited,
3;
Y. Sai,
Hutchison Medipharma Limited,
3;
X. Li,
Hutchison Medipharma Limited,
3;
W. Su,
Hutchison Medipharma Limited,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hm-0523-a-novel-syk-inhibitor-significantly-ameliorates-the-severity-of-arthritis-in-rodents/