Some small molecules in the pipeline

As we were talking about Tofacitinb during the past days, I grew eager to look again into the abstracts of last year’s ACR meeting for other potential drug candidates in the pipeline. Here’s what I’ve found.


VX-509, An Orally Available Janus Kinase 3 (JAK3) Specific Inhibitor, Showed Robust Activity in Pre-Clinical Models
Thomas Hoock and colleagues presented VX-509, an inhibitor of JAK3. The tested VX-509 in a rat model of rheumatoid arthritis (CIA), which showed a dose-dependent reduction in ankle swelling and other parameters exceeding the reference standard etanercept. “In the mouse oxazolone DTH model, VX-509 displayed dosedependent effects in alleviating the T-cell mediated skin inflammatory response, which was comparable to the reference standard prednisolone.” The authors concluded that the result support clinical testing of VX-509, which is already under way for rheumatoid arthritis.


[MON 1136]
VX-509, An Orally Available Janus Kinase 3 (JAK3) Specific Inhibitor, Showed Robust Activity in Pre-Clinical Models of Aberrant Immune/ Inflammatory Function.
Thomas Hoock1, James Hogan1, Sudipta Mahajan1, Dina Shlyakhter1, Luke Oh2, Larry Park2, George Ku2, Ian Catlett1,
Meryll Corbin1, Francesco Salituro2 and Mark Namchuk1.
1Vertex Pharmaceuticals Incorporated, Cambridge, MA, 2Formerly of Vertex Pharmaceuticals Incorporated, Cambridge, MA
Conclusion: Overall, VX-509 is a JAK3-specific inhibitor that was effective in several preclinical models of aberrant immune/inflammatory function with oral dosing that support BID and QD regimens. These results support the clinical testing of VX-509 in chronic, autoimmune/inflammatory disorders and VX-509 is currently undergoing clinical evaluation in rheumatoid arthritis.



HM-018, An Oral Small Molecule JAK Inhibitor, Ameliorates Experimental Autoimmune Encephalomyelitis (EAE) in Mice
Yu Cai and colleagues tested HM-018 in a mouse model for multiple sclerosis. As they presented their paper at the ACR meeeting one might speculate that parallel tests are under way for other animal models (rheumatoid arthritis). The results showed significant efficacy. The authors concluded that JAK inhibitors should be developped for the treatment of MS patients. They left us in the dark testing for efficacy in rheumatoid arthritis models, however.


[TUE 1958]
HM-018, An Oral Small Molecule JAK Inhibitor, Ameliorates Experimental Autoimmune Encephalomyelitis (EAE) in Mice.
Yu Cai1, Wuzhong Shen1, Qianqian Dong1, Zhipeng Wu1, Xiaoning Yang1, Ping Ren1, Youjun Yu1, Hongxia Shen1, Jia Li1, Jian Wang1, Yang Sai1, James Yan1, Wei Deng1, Jianguo Ji2, Weiguo Su1 and Haoran Zhao1.
1Hutchison Medipharma Limited, Shanghai, China, 2Abott, Shanghai, China
Conclusion: We demonstrated for the first time that HM-018, a potent and selective JAK inhibitor with attractive oral drug-like properties, exhibited strong beneficial effects under both prophylactic and therapeutic conditions in EAE models. These results support further development of JAK inhibitors for the treatment of MS patients.



A Novel SYK Specific Inhibitor for the Treatment of Rheumatoid Arthritis
Eun-Ho Lee and colleagues tested SKI-O-259, a novel oral SYK-specific inhibitor, out in the mouse CIA model. “Orally administered SKI-O-259 showed significant and dose-dependent inhibition of paw edema comparable to a reference in the mouse CIA models.” They concluded that SKI-O-259 is a candidate for a drug against rheumatoid arthritis.


[SUN 437]
A Novel SYK Specific Inhibitor for the Treatment of Rheumatoid Arthritis.
Eun-Ho Lee1, Sun-Hwa Chang1, Hae Jun Hwang1, Jang-Sik Choi1, Dong Sik Jung1, Sung Ho Park1, Sun Ju Wang1, Il Hwan Yang1, Sang Yeop Lee1, Jung-Ho Kim1, Ho-Juhn Song2, Jaekyoo Lee2, Jong Sung Koh2, Se Won Kim1 and Jung Kun Kim1.
1OSCOTEC Inc., Choongnam, South Korea, 2GENOSCO, Cambridge, MA
Conclusion: Our results suggest that SKI-O-259 is a potent SYK inhibitor with high target selectivity and feasibility under physiologically relevant condition of serum and ATP. SKI-O-259 showed a potent anti-arthritis effect after oral administration along with a good pharmacokinetic and safety profiles. Therefore, SKI-O-259 is a novel and potential candidate for orally available RA drug.




A Novel, Highly Selective Syk Kinase Inhibitor Significantly Ameliorates the Severity of Arthritis in Rodents
Zhong Cui Sun and colleagues presented data on HM-029, another orally available small molecule inhibitor for Syk kinase. They used mouse and rat models, the CIA model (collagen induced arthritis) in mice and the AA model (adjuvant arthritis) in Lewis rats. In the mouse model HM-029 significantly reduced disease severity, and the effect was dose dependent. In the rat model HM-029 showe amelioration of disease severity. The authors concluded that HM-029 is a promising candicate for the treatment of rheumatoid arthritis


[TUE 2084]
A Novel, Highly Selective Syk Kinase Inhibitor Significantly Ameliorates the Severity of Arthritis in Rodents.
Zhong Cui Sun1, Yu Cai1, Yan Qiu1, Lei Fang1, Xiaoming Dai1, Zhipeng Wu1, Ping Ren1, Jianlin He1, Changwu Lu1, Yongjuan Yu1, Jian Wang1, Yang Sai1, James Yan1, Jia Li1, Wei Deng1, Weihan Zhang1, Jianguo Ji2, Weiguo Su1 and Haoran Zhao1.
1Hutchison Medipharma Limited, Shanghai, China, 2Abott, Shanghai, China
Conclusion: 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.




So we have three more candidates for small molecule drugs:
     • VX-509, an orally available JAK-specific inhibitor
     • SKI-O-259, an orally available SYK-specific inhibitor
     • HM-029, an orally available SYK-specific inhibitor




Older blog entries about related topics


Fostamatinib is an oral spleen tyrosine kinase inhibitor http://rheumatologe.blogspot.de/2011/11/fostamatinib.html 

An Oral S1P Lyase Inhibitor [LX3305 (LX2931)] http://rheumatologe.blogspot.de/2011/11/oral-s1p-lyase-inhibitor-lx3305-lx2931.html  


Tofacitinib (CP-690,550) is an oral Janus Kinase Inhibitor http://rheumatologe.blogspot.de/2011/11/tofacitinib-oral-janus-kinase-inhibitor.html  


New kids on the block – Emerging therapies in rheumatology EULAR 2011 Meeting in London
8. Oral JAK-Inhibitor, “small molecules”, SYK-Inhibitor and others http://rheumatologe.blogspot.de/2011/10/new-kids-on-block-emerging-therapies-in.html