Zeng Yanqun, Cao Ruiyuan, Zhang Tianhong, Li Song, Zhong Wu
Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China; Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing, 100850, China.
Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing, 100850, China.
Eur J Med Chem. 2015 Jun 5;97:19-31. doi: 10.1016/j.ejmech.2015.04.043. Epub 2015 Apr 21.
HSP70 is a potential target for tumour treatment. HSP70 plays significant roles in several biological processes, including the regulation of apoptosis. In this study, piperidine derivatives were designed as novel HSP70 inhibitors based on virtual fragment screening performed in Dock 4.0, Discovery Studio 2.5 and SYBYL 6.9. A total of 67 novel piperidine derivatives were synthesized. Cell viability assays were performed in 16 cancer cell lines. The emphasis was placed on lapatinib-resistant breast cancer cells (BT/Lap(R)1.0, MDA-MB-361, SK/Lap(R)1.0, and MDA-MB-453). The compounds HSP70-36/37/40/43/46 significantly inhibited the proliferation of human breast cancer cells. Compound HSP70-36 inhibited the growth of BT474 and BT/Lap(R)1.0 cells with IC50 values of 1.41 μM and 1.47 μM, respectively. The binding affinity of HSP70-36/HSP70 was evaluated by surface plasmon resonance and yielded Kd values of 2.46 μM. The LD50 was 869.0 mgkg(-1). These data suggest that HSP70-36 may be a potential candidate compound for tumour treatment.
热休克蛋白70（HSP70）是肿瘤治疗的一个潜在靶点。HSP70在多个生物学过程中发挥重要作用，包括细胞凋亡的调控。在本研究中，基于在Dock 4.0、Discovery Studio 2.5和SYBYL 6.9中进行的虚拟片段筛选，设计了哌啶衍生物作为新型HSP70抑制剂。共合成了67种新型哌啶衍生物。在16种癌细胞系中进行了细胞活力测定。重点研究了拉帕替尼耐药的乳腺癌细胞（BT/Lap(R)1.0、MDA-MB-361、SK/Lap(R)1.0和MDA-MB-453）。化合物HSP70-36/37/40/43/46显著抑制人乳腺癌细胞的增殖。化合物HSP70-36抑制BT474和BT/Lap(R)1.0细胞的生长，IC50值分别为1.41 μM和1.47 μM。通过表面等离子体共振评估HSP70-36/HSP70的结合亲和力，得到的解离常数（Kd）值为2.46 μM。半数致死量（LD50）为869.0 mgkg(-1)。这些数据表明，HSP70-36可能是一种潜在的肿瘤治疗候选化合物。
