NF-kB inducing kinase (NIK, MAP3K14) is a key regulator of the non-canonical NF-kB pathway which is central to multiple autoimmune and inflammatory disorders. Modulation of this pathway through inhibition of NIK could offer significant therapeutic potential for certain autoimmune diseases while sparing the canonical NF-kB pathway to preserve acute responses to infection. Our method of targeting NIK was centered around a fragment-based approach aimed at producing highly efficient inhibitors with ideal physiochemical properties. Fragment-based screening was performed using biochemical assay, STD NMR and thermal shift assays which resulted in the identification of &gt;90 hits. A scaffold hopping strategy was employed to provide multiple potent series. Herein, we describe the discovery and optimization of a low MW fragment hit to a novel,efficient and selective NIK inhibitors.<br/><br/>NF-kB-inducing kinase (NIK, MAP3K14), is a central signalling component of the non-canonical NF-kB pathway, and is a key node in pathways activated in multiple autoimmune and inflammatory disorders. NIK is a crystallographically enabled target which contains a selectivity pocket which can be accessed through a narrow region defined by the gatekeeper Met471. To date, inhibitors of NIK have relied on a narrow series of alkynyl alcohol bearing chemo-types for its selective inhibition. These structures were arrived by rational design to exploit certain unique structural features of the enzyme; however incorporation of these functionalities has resulted in poor physiochemical and pharmacokinetic properties. The internal alkyne, although currently not viewed as a structural alert, may also pose a metabolic risk.<br/><br/>Modulation of this pathway and inhibition of NIK has been of keen interest for pharmaceutical companies including Takeda. We approached targeting NIK with a FBDD campaign in order to obtain novel lead matter, and to obtain inhibitors with better physiochemical properties. A fragment based screen against the target was performed using STD, NMR and thermal shift assays which resulted in identification &gt;90 hits. In this presentation, we disclose a recent FBDD optimization effort based on a fragment flip which allowed for the development of a novel non-alkyne NIK inhibitor.

Optimization of NK-kB inducing kinase inhibitors: A fragment based approach

255th National Meeting (2018)

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