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

• Published in: iScience Vol. 23; no. 9; p. 101474
• Main Authors: Singh, Vibha, Bhoir, Siddhant, Chikhale, Rupesh V., Hussain, Javeena, Dwyer, Donard, Bryce, Richard A., Kirubakaran, Sivapriya, De Benedetti, Arrigo
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 25.09.2020; Elsevier
• Subjects: Cancer; Medical Biochemistry; Structural Biology; Medical Biochemistry; Structural Biology; Cancer
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2020.101474

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. [Display omitted] •J54, a safe and potent inhibitor of TLK1, was generated via in silico docking 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 PCa Medical Biochemistry; Structural Biology; Cancer