Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
A Novel, Highly Selective Syk Kinase Inhibitor Significantly Ameliorates the Severity of Arthritis in Rodents.
Sun1, Zhong Cui, Cai1, Yu, Qiu1, Yan, Fang1, Lei, Dai1, Xiaoming, Wu1, Zhipeng, Ren1, Ping
SYK non receptor tyrosine kinase 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 Fcgamma chain, and other ITAM-containing C-type lectin and integrin receptors. In this study we seek to discover a highly potent and selective, orally available small molecule inhibitor for Syk kinase and evaluate its effects in rodent models of arthritis.
Using both in vitro enzymatic and cell-based assays and in vivo pharmacological assays for establishing structure-activity relationships, compounds were synthesized and screened to identify the ones with excellent potency, selectivity, and drug-like properties. Mouse collagen induced arthritis (CIA) was induced in DBA/1 mice by intradermal administration of chicken collagen type II (CCII) with complete Freund's adjuvant (CFA) on days 0 and 21. Paws were scored using a 04 scale with a maximum score of 16 for each animal. Rat adjuvant arthritis (AA) was induced in Lewis rats by intradermal administration of CFA on day 0. Paw volumes were measured daily after arthritis onset. In both models, HM-029 was administered by daily oral gavage.
HM-029 was discovered as a potent and highly selective inhibitor of Syk. It has been tested against a panel of 24 representative tyrosine and serine-threonine kinases and exhibited good general selectivity against other kinases, including KDR, JAK, and Src kinases. In bone marrow-derived mast cells (BMMCs), HM-029 potently inhibited IgE receptor cross-linking stimulated phosphorylation of LAT, ERK, p38 and Akt. The secretion of IL-6, TNFa and IL-13 was blocked by HM-029 as well. In mice with collagen-induced arthritis, treatment with HM-029 after disease onset significantly reduced disease severity in a dose dependent manner. Consistent with its efficacy in mice, HM-029 administered to rats with established AA also ameliorated disease severity compared to vehicle group.
This study showed that HM-029, acting through selective inhibition of Syk activation, exhibited strong beneficial effect in rodent arthritis models. These results support the development of HM-029 as a promising new agent for the treatment of rheumatoid arthritis.
To cite this abstract, please use the following information:
Sun, Zhong Cui, Cai, Yu, Qiu, Yan, Fang, Lei, Dai, Xiaoming, Wu, Zhipeng, et al; A Novel, Highly Selective Syk Kinase Inhibitor Significantly Ameliorates the Severity of Arthritis in Rodents. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2084