title: Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold.
abstract: A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC-3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10 nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3β protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC50value of 3.1 ± 0.1 μm than positive control (15.5 ± 0.4 μm). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
authors.forename: Dezhi
authors.identifier: http://orcid.org/0000-0002-5883-402X
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Tong
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Oral and Maxillofacial Surgery, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Fenghe
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
authors.forename: Guisen
authors.initials: G
authors.lastname: Zhao
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt1 inhibitors; GSK3β; antiproliferative activity; indole scaffold