Activated Cdc42-associated kinase 1 (ACK1) alterations have been considered to mediate bypass acquired resistance to the third-generation EGFR inhibitors (ASK120067 and osimertinib) in NSCLC. Despite many efforts to develop ACK1 small molecule inhibitors, no selective inhibitors have entered clinical trials. We used structure-based drug design to obtain a series of (R)-8-((tetrahydrofuran-2-yl)methyl)pyrido [2,3-d]pyrimidin-7-ones as novel selective ACK1 inhibitors. One of the representative compounds, 10zi, potently inhibited ACK1 kinase with an IC₅₀ of 2.1 nM, while sparing SRC kinase (IC₅₀ = 218.7 nM). Further, 10zi displayed good kinome selectivity in a profiling of 468 kinases. In the ASK120067-resistant lung cancer cell line (67R), 10zi dose-dependently inhibited the phosphorylation of ACK1 and downstream AKT pathway and showed a strong synergistic anti-tumor effect in combination with ASK120067 in vitro. Additionally, 10zi also exhibited reasonable PK profiles with an oral bioavailability of 19.8% at the dose of 10 mg/kg, which provided a promising lead for further development of new anticancer drugs.

中文翻译：

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(R)-8-((四氢呋喃-2-基)甲基)吡啶并[2,3-d]嘧啶-7-酮的设计、合成和评估作为新型选择性ACK1抑制剂来对抗第三代获得性耐药性EGFR抑制剂

激活的 Cdc42 相关激酶 1 (ACK1) 改变被认为可介导 NSCLC 中对第三代 EGFR 抑制剂（ASK120067 和奥希替尼）的旁路获得性耐药。尽管为开发ACK1小分子抑制剂做出了许多努力，但尚未有选择性抑制剂进入临床试验。我们采用基于结构的药物设计获得了一系列( R )-8-((四氢呋喃-2-基)甲基)吡啶并[2,3- d ]嘧啶-7-酮作为新型选择性ACK1抑制剂。代表性化合物之一10zi能有效抑制 ACK1 激酶，IC ₅₀为 2.1 nM ，同时不影响 SRC 激酶 (IC ₅₀ = 218.7 nM)。另外，10zi在 468 种激酶的分析中显示出良好的激酶组选择性。在ASK120067耐药肺癌细胞系（67R）中，10zi剂量依赖性地抑制ACK1和下游AKT通路的磷酸化，并在体外与ASK120067联合显示出强大的协同抗肿瘤作用。此外，10zi还表现出合理的PK曲线，在10 mg/kg剂量下，口服生物利用度为19.8%，这为进一步开发新的抗癌药物提供了良好的先导。