Identification of Inhibitors of the Lipid Kinase PI5P4Ka/B as Potential Anti-Cancer Agents

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The NCATS Early Translation Branch (ETB) hosts a broad and comprehensive program for the discovery of drug candidates directed towards rare diseases and pharmacological tools to probe the function of the human genome. ETB conducts research to understand the underlying principles driving the translation of basic research discoveries into tangible improvements in human health. The collaborative team previously uncovered novel inhibitors of the lipid kinase PI5P4Ka/B as potential anti-cancer agents indications. After an extensive SAR campaign against PI5P4Ka and b, the team demonstrated that a key dual PI5P4Ka/b inhibitor can kill p53 mutant cancer cells under conditions where autophagy is upregulated. This has led to several SAR campaigns to develop bioavailable dual inhibitors of PI5P4K alpha and beta. The team has begun development of PROTACs to further explore the intended therapeutic modality.