Features from a high throughput screening (HTS) hit and a previously reported scaffold were combined to generate naphthyridones <b>1 </b>as novel KDM5A enzyme inhibitors (IC<sub>50 </sub>= 0.025 µM). These naphthyridones were found to be 2-OG competitive inhibitors and selective over KDM4C and KDM2B enzymes. An X-ray co-crystal structure of a representative molecule bound to KDM5A was consistent with the observed inhibition mechanism.

Design and evaluation of naphthyridones as novel KDM5A inhibitors

251st National Meeting (2016)

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