Discovery and Optimization of a Novel Series of Dyrk1B Kinase Inhibitors To Explore a MEK Resistance Hypothesis

Potent and selective inhibitors of Dyrk1B kinase were developed to explore the hypothesis, based on siRNA studies, that Dyrk1B may be a resistance mechanism in cells undergoing a stress response

Discovery of 4‑Amino‑<i>N</i>‑[(1<i>S</i>)‑1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7<i>H</i>‑pyrrolo[2,3‑<i>d</i>]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases

Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target