Competition update from Portola's syk program
portola.com
>> J Pharmacol Exp Ther. 2012 Feb;340(2):350-9. Epub 2011 Oct 31.Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis.
Coffey G, Deguzman F, Inagaki M, Pak Y, Delaney SM, Ives D, Betz A, Jia ZJ, Pandey A, Baker D, Hollenbach SJ, Phillips DR, Sinha U.
SourcePortola Pharmaceuticals, 270 East Grand Ave., South San Francisco, CA 94080. usinha@portola.com.
AbstractBased on genetic studies that establish the role of spleen tyrosine kinase (Syk) in immune function, inhibitors of this kinase are being investigated as therapeutic agents for inflammatory diseases. Because genetic studies eliminate both adapter functions and kinase activity of Syk, it is difficult to delineate the effect of kinase inhibition alone as would be the goal with small-molecule kinase inhibitors. We tested the hypothesis that specific pharmacological inhibition of Syk activity retains the immunomodulatory potential of Syk genetic deficiency. We report here on the discovery of (4-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-2-((1R,2S)-2-aminocyclohexylamino) pyrimidine-5-carboxamide acetate (P505-15), a highly specific and potent inhibitor of purified Syk (IC(50) 1-2 nM). In human whole blood, P505-15 potently inhibited B cell antigen receptor-mediated B cell signaling and activation (IC(50) 0.27 and 0.28 µM, respectively) and Fce receptor 1-mediated basophil degranulation (IC(50) 0.15 µM). Similar levels of ex vivo inhibition were measured after dosing in mice (Syk signaling IC(50) 0.32 µM). Syk-independent signaling and activation were unaffected at much higher concentrations, demonstrating the specificity of kinase inhibition in cellular systems. Oral administration of P505-15 produced dose-dependent anti-inflammatory activity in two rodent models of rheumatoid arthritis. Statistically significant efficacy was observed at concentrations that specifically suppressed Syk activity by ~67%. Thus specific Syk inhibition can mimic Syk genetic deficiency to modulate immune function, providing a therapeutic strategy in P505-15 for the treatment of human diseases.<<
>> Blood. 2011 Nov 3;118(18):5000-10. Epub 2011 Aug 31.
Critical role for Syk in responses to vascular injury.
Andre P, Morooka T, Sim D, Abe K, Lowell C, Nanda N, Delaney S, Siu G, Yan Y, Hollenbach S, Pandey A, Gao H, Wang Y, Nakajima K, Parikh SA, Shi C, Phillips D, Owen W, Sinha U, Simon DI.
SourcePortola Pharmaceuticals Inc, South San Francisco, CA, USA.
AbstractAlthough current antiplatelet therapies provide potent antithrombotic effects, their efficacy is limited by a heightened risk of bleeding and failure to affect vascular remodeling after injury. New lines of research suggest that thrombosis and hemorrhage may be uncoupled at the interface of pathways controlling thrombosis and inflammation. Here, as one remarkable example, studies using a novel and highly selective pharmacologic inhibitor of the spleen tyrosine kinase Syk [PRT060318; 2-((1R,2S)-2-aminocyclohexylamino)-4-(m-tolylamino)pyrimidine-5-carboxamide] coupled with genetic experiments, demonstrate that Syk inhibition ameliorates both the acute and chronic responses to vascular injury without affecting hemostasis. Specifically, lack of Syk (murine radiation chimeras) attenuated shear-induced thrombus formation ex vivo, and PRT060318 strongly inhibited arterial thrombosis in vivo in multiple animal species while having minimal impact on bleeding. Furthermore, leukocyte-platelet-dependent responses to vascular injury, including inflammatory cell recruitment and neointima formation, were markedly inhibited by PRT060318. Thus, Syk controls acute and long-term responses to arterial vascular injury. The therapeutic potential of Syk may be exemplary of a new class of antiatherothrombotic agents that target the interface between thrombosis and inflammation.<<
Biogen bought into this program this past October. Note these abstracts deal with compounds that don't appear to be in clinical development. Looks like you'd have to ask the company for a reprint of the article related to the lead compound in this program, which was presented at an esoteric chemistry conference last year. I can't find the abstract anywhere. "Discovery of PRT062607: A potent and selective Syk inhibitor for the treatment of inflammatory, B cell proliferative diseases and thrombosis." Perhaps publication of the P1 data will shed more light on it in the near future. There are also patents to go sniff for, but I don't have the time for that right now.
Cheers, Tuck |
