Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy

iScience

卷:23

Rupesh V. Chikhale¹  Donard Dwyer²  Siddhant Bhoir³  Vibha Singh³  Richard A. Bryce⁴  Sivapriya Kirubakaran⁵  Javeena Hussain⁶  Arrigo De Benedetti⁶ 

[1] Department of Biological Engineering, Indian Institute of Technology Gandhinagar, Gandhinagar, India;

[2] Optometry, University of Manchester, Manchester, UK;

[3] Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, USA;

[4] Department of Chemistry, Indian Institute of Technology Gandhinagar, Gandhinagar, India;

[5] Department of Psychiatry and Behavioral Medicine, LSU Health Sciences Center, Shreveport, USA;

[6] Division of Pharmacy &

关键词: Medical Biochemistry;    Structural Biology;    Cancer;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: Through in vitro kinase 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 apoptosis in vitro and 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 and C. elegans.

【 授权许可】

Unknown