The Bag-1 inhibitor, Thio-2, reverses an atypical 3D morphology driven by Bag-1L overexpression in a MCF-10A model of ductal carcinoma in situ

Papadakis, EmmanouilL S.; Barker, Caroline; Syed, Huma; Reeves, Thomas; Schwaiger, Stefan; Stuppner, Hermann; Troppmair, Jakob; Blaydes, Jeremy P.; Cutress, Ramsey I.

doi:10.1038/oncsis.2016.10

Cited by 5 publications

(4 citation statements)

References 44 publications

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“…We have previously reported that Thio-2, a small molecule with a 2-arylbenzothiazole scaffold, inhibits the binding of BAG1L to the AR and the proliferation of AR-positive LNCaP cells . As Thio-2 is nonselective, − we synthesized 47 derivatives with different substitutions in the benzothiazole (building block A) and aryl (building block B) moieties in an attempt to make it more selective. This generated 17 compounds of type A1B, 14 of type A2B, five of type A3B, and 11 of type A4B (Figure A and Table S1).…”

Section: Resultsmentioning

confidence: 99%

Development of a Benzothiazole Scaffold-Based Androgen Receptor N-Terminal Inhibitor for Treating Androgen-Responsive Prostate Cancer

et al. 2021

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All current clinically approved androgen deprivation therapies for prostate cancer target the C-terminal ligand-binding domain of the androgen receptor (AR). However, the main transactivation function of the receptor is localized at the AR Nterminal domain (NTD). Targeting the AR NTD directly is a challenge because of its intrinsically disordered structure and the lack of pockets for drugs to bind. Here, we have taken an alternative approach using the cochaperone BAG1L, which interacts with the NTD, to develop a novel AR inhibitor. We describe the identification of 2-(4-fluorophenyl)-5-(trifluoromethyl)-1,3-benzothiazole (A4B17), a small molecule that inhibits BAG1L−AR NTD interaction, attenuates BAG1L-mediated AR NTD activity, downregulates AR target gene expression, and inhibits proliferation of AR-positive prostate cancer cells. This compound represents a prototype of AR antagonists that could be key in the development of future prostate cancer therapeutics.

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Section: Resultsmentioning

confidence: 99%

Development of a Benzothiazole Scaffold-Based Androgen Receptor N-Terminal Inhibitor for Treating Androgen-Responsive Prostate Cancer

et al. 2021

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“…To test if pharmacological interference of the BAG domain of Bag-1L would indeed impair AR action, we tested the efficacy Thio-2, a tool compound BAG domain inhibitor. Thio-2 has previously been postulated to bind to the BAG domain and to inhibit the interaction between Hsp70 and Bag-1 ( Enthammer et al, 2013 ; Papadakis et al, 2016 ). A consequence of this is the reduce growth of breast cancer cells, but so far this compound has not been tested in PCa.…”

Section: Resultsmentioning

confidence: 99%

“…This notion is supported by our findings pointing to a druggable pocket within the BAG domain of Bag-1L, which overlaps our triple mutation (CMut). An inhibitor (Thio-2) that targets the BAG domain was shown to be efficacious in blocking the antiapoptotic action of Bag-1 in breast cancer and melanoma cells ( Enthammer et al, 2013 ; Papadakis et al, 2016 ). In the present study we show that it is also effective in inhibiting the Bag-1L BAG:AR tau-5 interaction and suppressing PCa cell growth.…”

Section: Discussionmentioning

confidence: 99%

Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer

Cato

Neeb

Sharp

et al. 2017

eLife

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Targeting the activation function-1 (AF-1) domain located in the N-terminus of the androgen receptor (AR) is an attractive therapeutic alternative to the current approaches to inhibit AR action in prostate cancer (PCa). Here we show that the AR AF-1 is bound by the cochaperone Bag-1L. Mutations in the AR interaction domain or loss of Bag-1L abrogate AR signaling and reduce PCa growth. Clinically, Bag-1L protein levels increase with progression to castration-resistant PCa (CRPC) and high levels of Bag-1L in primary PCa associate with a reduced clinical benefit from abiraterone when these tumors progress. Intriguingly, residues in Bag-1L important for its interaction with the AR AF-1 are within a potentially druggable pocket, implicating Bag-1L as a potential therapeutic target in PCa.

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“…In general, BAG-1 is expressed at low levels in human tissues (Takayama et al 1998), but is frequently overexpressed in invasive cancers (Papadakis et al 2016;Takayama et al 1998; Electronic supplementary material The online version of this article (doi:10.1007/s12192-016-0751-z) contains supplementary material, which is available to authorized users. et al 1999).…”

Section: Introductionmentioning

confidence: 99%

UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1

Poulsen

Kampmeyer

Kriegenburg

et al. 2017

Cell Stress and Chaperones

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As a result of exposure to stress conditions, mutations, or defects during synthesis, cellular proteins are prone to misfold. To cope with such partially denatured proteins, cells mount a regulated transcriptional response involving the Hsf1 transcription factor, which drives the synthesis of molecular chaperones and other stress-relieving proteins. Here, we show that the fission yeast Schizosaccharomyces pombe orthologues of human BAG-1, Bag101, and Bag102, are Hsp70 co-chaperones that associate with 26S proteasomes. Only a subgroup of Hsp70-type chaperones, including Ssa1, Ssa2, and Sks2, binds Bag101 and Bag102 and key residues in the Hsp70 ATPase domains, required for interaction with Bag101 and Bag102, were identified. In humans, BAG-1 overexpression is typically observed in cancers. Overexpression of bag101 and bag102 in fission yeast leads to a strong growth defect caused by triggering Hsp70 to release and activate the Hsf1 transcription factor. Accordingly, the bag101-linked growth defect is alleviated in strains containing a reduced amount of Hsf1 but aggravated in hsp70 deletion strains. In conclusion, we propose that the fission yeast UBL/BAG proteins release Hsf1 from Hsp70, leading to constitutive Hsf1 activation and growth defects.

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The Bag-1 inhibitor, Thio-2, reverses an atypical 3D morphology driven by Bag-1L overexpression in a MCF-10A model of ductal carcinoma in situ

Cited by 5 publications

References 44 publications

Development of a Benzothiazole Scaffold-Based Androgen Receptor N-Terminal Inhibitor for Treating Androgen-Responsive Prostate Cancer

Development of a Benzothiazole Scaffold-Based Androgen Receptor N-Terminal Inhibitor for Treating Androgen-Responsive Prostate Cancer

Development of Bag-1L as a therapeutic target in androgen receptor-dependent prostate cancer

UBL/BAG-domain co-chaperones cause cellular stress upon overexpression through constitutive activation of Hsf1

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