Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (<0.01 mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6, with beneficial physicochemical parameters (CLogP = 2.56, solubility in water ≈ 0.1 mg/ml) meeting the principles of oral drugs. B6 exhibited anti-proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC₅₀ = 0.92 ± 0.19 μM) and HCC827 (Del119 IC₅₀ = 0.014 ± 0.01 μM). Moreover, B6 significantly slowed down H1975 tumor growth with anti-tumor rate of 73.9% (p < 0.01). Enzyme potencies assay demonstrated B6 moderately selectively inhibited Bmx (IC₅₀ = 35.7 ± 0.1 nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance.

被描述为Btk抑制剂的依鲁替尼还有效抑制肺癌的两个良好靶标Bmx和EGFR。由于其高CLogP（4.07）和低水溶性（<0.01 mg / ml），导致不利的生物利用度，依鲁替尼需要高剂量才能在非小细胞肺癌（NSCLC）的治疗中获得良好的临床反应。在我们通过结构优化改善依鲁替尼的CLogP的努力中，发现了一种有效的抗癌剂B6，其有益的理化参数（CLogP = 2.56，在水中的溶解度≈0.1 mg / ml）符合口服药物的原理。B6对EGFR表达细胞，尤其是突变细胞如H1975（L858R / T790M，IC ₅₀ = 0.92±0.19μM）和HCC827（Del119 IC ₅₀  = 0.014±0.01μM）。此外，B6显着减慢了H1975肿瘤的生长，抗肿瘤率为73.9％（p  <0.01）。酶效能分析表明，B6 与其他激酶相比，对Bmx具有中等选择性的抑制作用（IC ₅₀ = 35.7±0.1 nM）。因此，作为有效的Bmx抑制剂，B6有望成为具有获得性耐药性的NSCLC的有效治疗方法。