JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family. They play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases. Particularly, pSTAT3 is observed in response to the treatment with inhibitors of oncogenic signaling pathways such as EGFR, MAPK, and AKT and is associated with resistance or poorer response to agents targeting these pathways. Among the JAK family kinases, JAK1 has been shown to be the primary driver of STAT3 phosphorylation and signaling; therefore, selective JAK1 inhibition can be a viable means to overcome such treatment resistances. Herein, an account of the medicinal chemistry optimization from the promiscuous kinase screening hit 3 to the candidate drug 21 (AZD4205), a highly selective JAK1 kinase inhibitor, is reported. Compound 21 has good preclinical pharmacokinetics. Compound 21 displayed an enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model.

中文翻译：

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（2R）-N- [3- [2-[（3-甲氧基-1-甲基-吡唑-4-基）氨基]嘧啶-4-基] -1H-吲哚-7-基] -2-的发现（4-甲基哌嗪-1-基）丙烯酰胺（AZD4205）作为有效的选择性Janus激酶1抑制剂。

JAK1，JAK2，JAK3和TYK2属于JAK（Janus激酶）家族。它们在细胞因子信号传导中起关键作用。JAK / STAT途径的组成性激活与多种疾病有关。特别地，在响应于致癌信号途径如EGFR，MAPK和AKT的抑制剂的治疗中观察到pSTAT3，其与针对这些途径的药物的抗性或较差的反应有关。在JAK家族激酶中，JAK1已被证明是STAT3磷酸化和信号转导的主要驱动因子。因此，选择性抑制JAK1可能是克服此类治疗耐药性的可行方法。这里，报道了从混杂激酶筛选命中3到高度选择性的JAK1激酶抑制剂候选药物21（AZD4205）的药物化学优化。化合物21具有良好的临床前药代动力学。在临床前非小细胞肺癌（NSCLC）异种移植NCI-H1975模型中，化合物21与批准的EGFR抑制剂osimertinib组合显示出增强的抗肿瘤活性。