Kirsten Bell

TL;DR: The essential role of Stat3 downstream of Jaks is demonstrated by inhibition of tumor growth using short hairpin RNA targeting Stat3, supporting a key role of Jak kinase activity in Stat3-dependent tumorigenesis.

TL;DR: The discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor are disclosed and are currently being evaluated in Phase I clinical trials.

TL;DR: Using the C-ring fragment from first clinical candidate AZD1480, optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor, which demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.

TL;DR: The design, synthesis and biological evaluation of a series of pyrazol-3-ylamino pyrazines as potent and selective JAK2 kinase inhibitors is reported, along with the pharmacokinetic and pharmacodynamic properties of lead compounds.

TL;DR: An account of the medicinal chemistry optimization from a promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective JAK1 kinase inhibitor, is reported, which has good preclinical pharmacokinetics and displayed an enhanced antitumor activity in combination with approved EGFR inhibitor, osimertinib, in a preclinical non-small cell lung cancer xenograft NCI-H1975 model.