He Linhong, Li Da, Zhang Chufeng, Bai Peng, Chen Lijuan
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China.
Bioorg Med Chem Lett. 2017 Sep 1;27(17):4171-4175. doi: 10.1016/j.bmcl.2017.07.009. Epub 2017 Jul 4.
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 (<0.01mg/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≈0.1mg/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, IC=0.92±0.19μM) and HCC827 (Del119 IC=0.014±0.01μM). 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 (IC=35.7±0.1nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance.
依鲁替尼被描述为一种布鲁顿酪氨酸激酶（Btk）抑制剂，它还能有效抑制Bmx和表皮生长因子受体（EGFR），这两个都是肺癌的良好靶点。由于依鲁替尼的辛醇/水分配系数（CLogP）较高（4.07）且水溶性较低（<0.01mg/ml），导致其生物利用度不佳，因此在治疗非小细胞肺癌（NSCLC）时，依鲁替尼需要高剂量才能达到良好的临床反应。我们通过结构优化来提高依鲁替尼的CLogP，从而发现了一种有效的抗癌药物B6，其有益的物理化学参数（CLogP = 2.56，水溶性≈0.1mg/ml）符合口服药物的原则。B6对表达EGFR的细胞，尤其是突变细胞，如H1975（L858R/T790M，半数抑制浓度（IC）= 0.92±0.19μM）和HCC827（缺失19外显子，IC = 0.014±0.01μM）表现出抗增殖活性。此外，B6显著减缓了H1975肿瘤的生长，抗肿瘤率为73.9%（p<0.01）。酶活性测定表明，与其他激酶相比，B6对Bmx具有适度的选择性抑制作用（IC = 35.7±0.1nM）。因此，作为一种有效的Bmx抑制剂，B6有可能成为治疗获得性耐药NSCLC的有效药物。
