Generation of phenothiazine with potent anti-TLK1 activity for prostate cancer therapy

Vibha Singh, Siddhant Bhoir, Rupesh Chikhale, Javeena Hussain, Donard Dwyer, Richard A. Bryce, Sivapriya Kirubakaran, Arrigo De Benedetti

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
11 Downloads (Pure)


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.
Original languageEnglish
Article number101474
Issue number9
Early online date20 Aug 2020
Publication statusPublished - 25 Sep 2020

Cite this