JAK1 together with JAK2, JAK3, and TYK2 belong to the JAK (Janus-associated kinase) family of cytoplasmic tyrosine kinases that play important roles in cytokine and growth factor mediated signal transduction. Activated by cytokine or growth factor engagement, JAKs are autophosphorylated to stimulate the recruitment and phosphorylation of the signal transducers and activators of transcription (STAT), leading to the dimerization and translocation of phosphorylated STATs into the nucleus and increasing cellular proliferation and resistance to apoptosis. Up to 70% of human cancers are linked to persistent elevated STAT3 activity that is associated with resistance or poorer response to chemotherapy agents and treatment with inhibitors of targeting oncogenic signalling pathways such as EGFR, MAPK and AKT. JAK1 is believed to be a primary driver of STAT3 phosphorylation and signalling. JAK2 is essential for the signal transduction downstream of erythropoietin, thrombopoietin and related receptors that control erythrocyte and megakaryocyte expansion. Therefore, JAK1 selective inhibition may enable improved target coverage of JAK1-STAT3 signalling by sparing toxicities such as thrombocytopenia and anaemia due to JAK2 inhibition. <br/>We will present our detailed medicinal chemistry optimization from a non-kinome selective screening hit to the candidate drug AZD4205, a highly selective novel JAK1 kinase inhibitor. AZD4205 displayed high levels of JAK1 biochemical and cellular potency with favourable physical properties and excellent preclinical in vivo pharmacokinetics. AZD4205, in a combination with low dose osimertinib, demonstrated a greater antitumor activity in an H1975 (T790M) NSCLC xenograft model. Furthermore, AZD4205 enhanced osimertinib-induced tumor regression in an LG1049 (T790M) NSCLC PDX model. These findings warrant the further clinical investigation of AZD4205 to fully understand its potential as an anti-cancer therapeutic.<br/>

Discovery of the JAK1 selective kinase inhibitor AZD4205

254th National Meeting (2017)

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