Study Sheds New Light on Tecfidera’s Inhibitory Mechanism of Action

Jose Marques Lopes, PhD avatar

by Jose Marques Lopes, PhD |

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Satb1 and inflammation

Multiple sclerosis (MS) treatment Tecfidera (dimethyl fumarate) binds to a specific amino acid in key enzymes to inhibit their activity, according to a study that sheds more light on this therapy’s little-known mechanism of action.

This newly identified regulatory mechanism may lead to the discovery of new compounds that could be used for treatment, the scientists suggest in the study, titled “Dimethyl fumarate is an allosteric covalent inhibitor of the p90 ribosomal S6 kinases” and published in the journal Nature Communications.

Dimethyl fumarate is an immunosuppressant treatment for both relapsing-remitting MS — marketed as Tecfidera by Biogen — and moderate to severe plaque psoriasis, approved in the EU and U.K. under the trade name Skilarence (by Almirall).

Although it is widely used, the treatment’s mechanism of action is still little understood, with clinical benefits only evident after weeks to months of high-dose administration. Among its possible mechanisms, it has been proposed that it inhibits the differentiation of specific immune T-cells (T helper cell 1 and 17) and reduces the recruitment of neutrophils — a type of white blood cell — in inflammation.

One of the ways in which Tecfidera inhibits T-cell differentiation is through suppressing cellular pathways mediated by the protein complex NF-κB, as it targets a specific site — the C-terminal kinase domain — of enzymes called ribosomal S6 kinases (RSKs) and mitogen- and stress-activated kinases (MSKs), both implicated in MS and psoriasis.

In particular, the two MSK variants (1 and 2) are produced at higher levels in cells of the central nervous system and immune system, where they regulate the expression of the anti-inflammatory molecule interleukin-10.

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Now, a team from Aarhus University in Denmark has conducted a high-resolution analysis on the crystal structure of the C-terminal kinase domain of the mouse p90 RSK2 in the presence of dimethyl fumarate.

The in vitro work showed that Tecfidera inhibits RSKs and MSKs by forming a type of bond called a covalent bond with the cysteine amino acid located at a type of regulatory site known as allosteric, which influences the enzyme’s active site. Binding of Tecfidera prevents the enzyme from binding to its substrate, and stabilizes an auto-inhibitory conformation, according to a press release from Aarhus University’s Department of Molecular Biology and Genetics.

“This interaction is likely to represent an important component of the mechanism of action of [Tecfidera] as a clinical drug,” the scientists wrote.

They further noted that the proposed mechanism is in accordance with the slow effectiveness of the treatment in patients. Although they say that Tecfidera may target other cellular components, they predicted that only a few would meet the structural requirements to bind this compound.

This specific mechanism of enzyme inhibition, which is different from those of cancer medications that also inhibit protein kinases, “invites a rational development of novel and more specific compounds,” the team wrote.