Selectivity remains a top challenge in the optimization of kinase inhibitors. In the &gt;20 years of kinase-directed drug discovery, researchers have developed numerous strategies in attempt to achieve selectivity for specific kinases over the &gt;500-membered kinome. This disclosure will highlight a potentially general strategy for rapid generation of selective tool compounds for individual methionine-gatekeeper kinases. Lead identification studies for Met-gatekeeper kinases NIK (NF-kB inducing kinase), class-II PAKs (p21-activating kinases) and PKD1 (protein kinase D1) will be presented. Potent and highly specific inhibitors of these kinases were quickly realized by leveraging a type 1.5 binding mode driven by a propargyl alcohol substituent. Structural hypotheses for key features contributing to the selectivity of these compounds will be discussed. An overview of further optimization of NIK-selective chemical matter to compounds utilized in advanced preclinical studies will be included.

Generating selective inhibitors of methionine-gatekeeper kinases: Case studies on NIK, PAKs and PKD1

255th National Meeting (2018)

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