Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
HM-A42, a Novel Inhibitor of IKK Kinase Reverses Clinical and Histological Disease Parameters in Multiple Autoimmune Disease Models.
Cai1, Yu, Wang1, Xinrong, Ren1, Ping, Lu1, Changwu, He1, Jianlin, Dai3, Xiaoming, Dong1, Qianqian
NF-kB activation has been demonstrated to be involved in the pathogenesis of multiple inflammatory diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), and respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). The central role that IkB kinase b (IKKb) plays in regulating NF-kB signaling in response to inflammatory stimuli has made this enzyme as an attractive target for therapeutic intervention. Here we report the identification and preclinical characterization of HM-A42, a potent, selective, and orally bioavailable inhibitor of IKKb kinase.
Methods and Results:
HM-A42 is a potent and highly selective inhibitor of IKKb kinase (IC50 = 0.0060.058uM) and demonstrated 127-fold selectivity against IKKa kinase. In OVA-induced asthma model in BN rat, HM-A42 treatment led to reduced inflammatory cell number in the BAL fluid with an ED50 of 0.49 mg/kg. In an acute PLP139151 peptide-induced EAE mouse model of MS, HM-A42 treatment resulted in rapid and substantial regression of EAE relapses. It also significantly reduced EAE clinical score in a dose dependent manner over a 6 week period with an ED50 of 3.7 mg/kg. Histopathological examination of the spinal cords showed that disease scores for inflammation and the area of demyelination were all significantly lower in HM-A42 treated animals versus vehicle control group. HM-A42 was also tested in a murine collagen-induced arthritis model of RA in a prophylactic setting. Oral administration of HM-A42 resulted in significant reduction of disease symptom that continued through the course of treatment with an ED50 of 4.3mg/kg. In addition, HM-A42 exhibited favorable pharmacokinetic profile including good oral absorption and bioavailability in various species and low potential for CYP450 inhibition. Moreover, from safety point of view, HM-A42 had low affinity for hERG and was negative in AMES test. Its no adverse effect level (NOAEL) was 500 mg/kg in rat, showing a big safety window over efficacy doses in multiple disease models.
The administration of HM-A42, a potent and highly selective IKKb kinase inhibitor, resulted in substantial efficacy in aggressive models of asthma, rheumatoid arthritis (RA) and multiple sclerosis (MS). These studies support further development of HM-A42 in clinical studies.
To cite this abstract, please use the following information:
Cai, Yu, Wang, Xinrong, Ren, Ping, Lu, Changwu, He, Jianlin, Dai, Xiaoming, et al; HM-A42, a Novel Inhibitor of IKK Kinase Reverses Clinical and Histological Disease Parameters in Multiple Autoimmune Disease Models. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1107