eprintid: 10121644
rev_number: 14
eprint_status: archive
userid: 608
dir: disk0/10/12/16/44
datestamp: 2021-02-15 16:22:21
lastmod: 2021-10-06 22:56:58
status_changed: 2021-02-15 16:22:21
type: article
metadata_visibility: show
creators_name: Singh, V
creators_name: Bhoir, S
creators_name: Chikhale, RV
creators_name: Hussain, J
creators_name: Dwyer, D
creators_name: Bryce, RA
creators_name: Kirubakaran, S
creators_name: De Benedetti, A
title: Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy
ispublished: pub
divisions: UCL
divisions: B02
divisions: C08
divisions: D10
keywords: Cancer, Medical Biochemistry, Structural Biology
note: © 2020 The Author(s).
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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.
date: 2020-08-20
date_type: published
official_url: http://dx.doi.org/10.1016/j.isci.2020.101474
oa_status: green
full_text_type: pub
pmcid: PMC7486443
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 1846466
doi: 10.1016/j.isci.2020.101474
pii: S2589-0042(20)30666-0
lyricists_name: Chikhale, Rupesh
lyricists_id: RCHIK73
actors_name: Salunke, Smita
actors_name: Harris, Jean
actors_id: SSALU59
actors_id: JAHAR68
actors_role: owner
actors_role: impersonator
full_text_status: public
publication: iScience
volume: 23
number: 9
article_number: 101474
event_location: United States
citation:        Singh, V;    Bhoir, S;    Chikhale, RV;    Hussain, J;    Dwyer, D;    Bryce, RA;    Kirubakaran, S;           Singh, V;  Bhoir, S;  Chikhale, RV;  Hussain, J;  Dwyer, D;  Bryce, RA;  Kirubakaran, S;  De Benedetti, A;   - view fewer <#>    (2020)    Generation of Phenothiazine with Potent Anti-TLK1 Activity for Prostate Cancer Therapy.                   iScience , 23  (9)    , Article 101474.  10.1016/j.isci.2020.101474 <https://doi.org/10.1016/j.isci.2020.101474>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10121644/1/Generation%20of%20Phenothiazine%20with%20Potent%20Anti-TLK1%20Activity%20for%20Prostate%20Cancer%20Therapy.pdf