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

Singh, Vibha, Bhoir, Siddhant, Chikhale, Rupesh ORCID:, Hussain, Javeena, Dwyer, Donard, Bryce, Richard A., Kirubakaran, Sivapriya and De Benedetti, Arrigo (2020) Generation of phenothiazine with potent anti-TLK1 activity for prostate cancer therapy. iScience, 23 (9). ISSN 2589-0042

[thumbnail of Published_Version]
PDF (Published_Version) - Published Version
Available under License Creative Commons Attribution.

Download (5MB) | Preview


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.

Item Type: Article
Uncontrolled Keywords: sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 16 Sep 2020 23:57
Last Modified: 22 Oct 2022 07:04
DOI: 10.1016/j.isci.2020.101474

Actions (login required)

View Item View Item