The Lemmings are off…S1P1 inhibitors

Lukas S, Patnaude L, Haxhinasto S, Slavin A, Hill-Drzewi M, Horan J, Modis LK.No Differences Observed among Multiple Clinical S1P1 Receptor Agonists (Functional Antagonists) in S1P1 Receptor Down-regulation and Degradation. J Biomol Screen. 2013 Sep. [Epub ahead of print]

Sphingosine-1-phosphate (S1P) is a bioactive metabolite with pleiotropic effects on multiple cellular processes in health and disease. Responses elicited by S1P are a result of binding to five specific G-protein-coupled receptors. We have developed multiple assays to systematically study the downstream signaling of these receptors, including early events such as direct receptor activation (GTPγS) as well as more distal events such as S1P1 receptor degradation. Employing such assays, we have characterized and compared multiple S1P1 agonists that are in clinical development including FTY720, BAF312, CS-0777, and other molecules from the S1P1 patent literature. Our parallel assessment has allowed us to compare their potency against S1P1, their selectivity against the four other S1P receptors, as well as species cross-reactivity. We note that all of the compounds studied signal in an identical manner through S1P1, leading to receptor degradation.

Drugs must be like wasp stings as they attract more, so the pharma lemmings are out there.Once one drug works, an alternative version follows so we first have Gilenya (FTY720). Novartis even follow in their own foot steps and make BAF312, but there are others and it is not just CS-0777.  You will see a load more at ECTRIMS. They all modulate S1P1 receptor so will they all work…probably. I bet there will not be a price war.

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