文章基本信息

标题：Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy
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作者：Vibha Singh ; Siddhant Bhoir ; Rupesh V. Chikhale 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：9
页码：1-39
DOI：10.1016/j.isci.2020.101474
语种：English
出版社：Elsevier
摘要：SummaryThroughin vitrokinase assays and docking studies, we report the synthesis and biological evaluation of a phenothiazine analog J54 with potent TLK1 inhibitory activity for prostate cancer (PCa) therapy. Most PCa deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa. Treatments that can suppress the conversion to mCRPC have high potential to be rapidly implemented in the clinics. ADT results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DNA damage response that typically results in temporary cell-cycle arrest of androgen-responsive PCa cells, whereas its abrogation leads to apoptosis. We studied J54 as a potent inhibitor of this axis and as a mediator of apoptosisin vitroand in LNCaP xenografts, which has potential for clinical investigation in combination with ADT. J54 has low affinity for the dopamine receptor in modeling and competition studies and weak detrimental behavioral effects in mice andC. elegans.Graphical AbstractDisplay OmittedHighlights•J54, a safe and potent inhibitor of TLK1, was generated viain silicodocking studies•J54 leads to apoptosis of PCa cells in combination with anti-androgen administration•J54 has low affinity for dopamine receptor and low anti-dopaminergic activity in animals•TLK1B is selectively increased upon ADT thereby providing a specific target for PCaMedical Biochemistry; Structural Biology; Cancer