4-Anilinoquinolines were identified as potent and narrow spectrum inhibitors of the cyclin G Associated Kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4-anilino group and the 6,7-quinoline substituents produced GAK inhibitors with nanomolar activity and high selectivity relative to other members of the Numb-Associated Kinase (NAK) sub-family. These compounds could be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious diseases. Our results demonstrate that quinoline-based ATP-competitive kinase inhibitors can be designed with exquisite selectivity within the NAK sub-family. Iterative medicinal chemistry led to a member of the 4-anilinoquinoline series with over 50,000-fold selectivity for GAK over other members of the NAK sub-family. Analogs within 4-anilinoquinolines series have the potential to yield high quality chemical probes for use in the elucidation of GAK function in cells and <i>in vivo</i>.

Identification and optimization of 4-anilinoquinolines as selective inhibitors of cyclin G associated kinase

254th National Meeting (2017)

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