ABSTRACT
Cyclin-dependent kinase 9 (CDK9) plays a role in transcriptional regulation, which had become an attractive target for discovery of antitumor agent. In this work, beyond traditional CDK9 inhibitor with bidentate ligands in ATP binding domain, a series of novel CDK9 inhibitor with tridentate ligand were designed and synthesized. Surprisingly, this unique tridentate ligand structure endows better CDK9 inhibition selectivity compared to other CDK subtypes, and the lead candidate compound Z4-7a showed effective proliferation inhibition in HCT116 cells with acceptable pharmacokinetic properties. Research on the mechanism indicated that Z4-7a could induce apoptosis in the HCT116 cell line by inhibiting phosphorylation of RNA polymerase II at Ser2, which resulted in the inhibition of apoptosis-related genes and proteins expression. In brief, introduction of tridentate ligand might work as a promising strategy for the development of novel selective CDK9 inhibitor.
Subject(s)
Antineoplastic Agents , Apoptosis , Cell Proliferation , Cyclin-Dependent Kinase 9 , Dose-Response Relationship, Drug , Drug Design , Protein Kinase Inhibitors , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Cyclin-Dependent Kinase 9/metabolism , Humans , Ligands , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Cell Proliferation/drug effects , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Molecular Structure , Apoptosis/drug effects , Drug Screening Assays, Antitumor , Drug Discovery , Animals , HCT116 CellsABSTRACT
BACKGROUND: The impact of the May 2008 Wenchuan earthquake, measuring a massive 8.0 on the surface wave magnitude scale, on public health in China has been significant and multifaceted. In light of extant data on prevalence and risk factors for posttraumatic stress disorder (PTSD) after other natural diasters, we collected data from the Wenchuan earthquake survivors to estimate the prevalence of PTSD and to characterize a range of PTSD risk factors. METHODS: A cross-sectional multicluster sample survey of 446 respondents (201 from the Qiang ethnic-minority group, 245 the majority Han Chinese group) was conducted in August 2008 in Beichuan county, Sichuan province, a region that was severely affected by the earthquake. In total, 240 households were represented, with a mean of 2.2 respondents per household. Data were collected from structured interviews and the Harvard Trauma Questionnaire (HTQ) and DSM-IV criteria were used to diagnose PTSD. RESULTS: The prevalence of PTSD was 45.5% (203/446). Low household income, being from an ethnic minority, living in a shelter or temporary house, death in family, and household damage were factors significantly related to increased odds of PTSD. CONCLUSIONS: PTSD is common after a major disaster. Postdisaster mental health recovery programs that include early identification, ongoing monitoring, preventive and intervention programs, and sustained psychosocial support are needed for the highest-risk population, namely, the bereaved, people without incomes and those with serious household damage. These populations may also benefit from governmental and nongovernmental programs that provide social and economic support, as suggested by earlier studies.