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the series of compounds seemed to lack specificity against other Src family kinases and Aurora B inhibitor lacked desirable pharmacokinetic properties. The pyrimidopyrazine derivative, 21, is reported for being a potent Lck inhibitor with IC50_2 Aurora B inhibitor nM. The cellular activity, selectivity against other Src family of kinases, and pharmacokinetic properties of 21 were less than optimal.

In an ex vivo anti CD3/CD 28 induced IL 2 production model in mice, orally administered 23 reduced BI-1356 serum IL 2 levels in a dose dependent manner with ED50_5 mg/kg. Compound 23, which has a desirable pharmacokinetic profile in rats, was efficacious in reducing paw swelling upon oral dosing at 3 mg/kg b. i. d. in a rat adjuvant arthritis model of established disease. The 2 amino 6 aryl quinazoline derivative, 24, is a potent Lck inhibitor that is not selective against other members of Src family kinases, p38, and VEGFR2. In a human whole blood assay, 24 inhibited the anti CD3/CD28 antibody induced IL 2 production with IC50_113 nM. Compound 24 had a desirable pharmacokinetic profile in rats and was orally efficacious in reducing serum levels of IL 2 in BALB/c mice with ED50_ 22 mg/kg.

In humans, mutations in JAK3 have been associated with severe combined immunodeficiency and JAK3 knockout mice are found to display BI-1356"href="http://www.selleckchem.com/products/linagliptin-bi-1356.html">BI-1356 defects in T, B, and NK cell development and function. Therefore, inhibition of JAK3 has potential applications in the treatment of inflammation, allergy, autoimmune disorders, and organ transplant rejection. A number of JAK3 inhibitors, such as WHI P131, WHI P154, and PNU156804, which are not highly selective against other members of the JAK family of kinases, have been reported and included in a review article. This review will focus on JAK3 inhibitors reported during 2006?2007 and the references cited here refer to the inhibitors reported earlier. A number of JAK3 inhibitors have been disclosed in an abstract, manuscript, or at scientific meetings without disclosing their structure and/or pharmacology profile, such inhibitors are not covered in this review.

CP 690550, a potent JAK3 inhibitor with in vitro enzyme inhibitory and cellular activity as described above, is found to inhibit JAK2 kinase significantly. The compound is found to exhibit profound immunosuppressive activity in a variety of animal models.