Singh, V;
Bhoir, S;
Chikhale, RV;
Hussain, J;
Dwyer, D;
Bryce, RA;
Kirubakaran, S;
(2020)
Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy.
iScience
, 23
(9)
, Article 101474. 10.1016/j.isci.2020.101474.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.isci.2020.101474 |
| Publisher version: | http://dx.doi.org/10.1016/j.isci.2020.101474 |
| Language: | English |
| Additional information: | © 2020 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Cancer, Medical Biochemistry, Structural Biology |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10121644 |
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