title: Design, synthesis and biological evaluation of novel HSP70 inhibitors: N, N'-disubstituted thiourea derivatives.
abstract: As novel heat shock protein 70 (HSP70) inhibitors, N, N'-disubstituted thiourea derivatives were designed and synthesized based on the X-ray structure of the ATPase domain (nucleotide binding domain, NBD). An ATPase activity inhibition assay revealed that these compounds effectively inhibited HSP70 ATPase activity. The results revealed that the compounds 370/371/374/379/380//392/394/397/404/405 and 407 can inhibit the HSP70 ATPase turnover with high percentages of inhibition: 50.42, 38.46, 50.45, 44.12, 47.13, 50.50, 40.95, 65.36, 46.23, 35.78, and 58.37 in 200 μM, respectively. Significant synergies with lapatinib were observed for compound 379 and compound 405 in the BT474 breast cancer cell line. A structure-function analysis revealed that most of the thiourea derivatives exhibited cooperative action with lapatinib in the BT474 cancer cell line and the BT/Lap(R)1.0 lapatinib-resistant cell line. HSP70 inhibitors may be developed as synergetic drugs in drug-resistant cancer therapy.
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing 100850, China; Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
authors.forename: Yan-Qun
authors.initials: YQ
authors.lastname: Zeng
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing 100850, China. Electronic address: 21cc@163.com.
authors.forename: Rui-Yuan
authors.initials: RY
authors.lastname: Cao
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing 100850, China.
authors.forename: Jian-Ling
authors.initials: JL
authors.lastname: Yang
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing 100850, China.
authors.forename: Xing-Zhou
authors.initials: XZ
authors.lastname: Li
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing 100850, China.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Laboratory of Computer-Aided Drug Design and Discovery, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Rd., Beijing 100850, China. Electronic address: zhongwu@bmi.ac.cn.
authors.forename: Wu
authors.initials: W
authors.lastname: Zhong
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004351:Drug Resistance; D004357:Drug Synergism; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D000072417:Protein Domains; D013890:Thiourea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D000251:Adenosine Triphosphatases; D013890:Thiourea
keywords: Anti-cancer; Combinatorial drug therapy; HSP70 inhibitors; SPR; Synergism