EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor

Mol, Eva De; Fenwick, R. Bryn; Phang, Christopher; Buzón, Víctor; Szulc, Elzbieta; Fuente, Alex de la; Escobedo, Albert; García, Jesús; Bertoncini, Carlos W.; Estébanez‐Perpiñá, Eva; McEwan, Iain J.; Riéra, Antoni; Salvatella, Xavier

doi:10.1021/acschembio.6b00182

Cited by 115 publications

(183 citation statements)

References 39 publications

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“…I-EPI-002 is 10 times more potent than EPI-002, which has IC 50 in the range of 10 μM for these cell-based assays (22, 23). Together, these data support that I-EPI-002 has improved potency compared with EPI-002 and are consistent with saturation transfer difference–NMR data, showing strong interaction of the bisphenyl rings of EPI with Tau-5 of AR AF-1 (24). …”

Section: Resultssupporting

confidence: 84%

“…EPI-002 and analogs bind to AR AF-1 (22, 23) and specifically to Tau-5 in the AF-1 region (24). Here, we show that 123 I-EPI-002 binds to recombinant full-length AR (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

“…Thus, there is an urgent need to develop clinical methods to determine expression of AR-Vs in metastatic CRPC. One possible approach is application of molecular imaging agents to detect AR-Vs. EPI small molecules provide an opportunity to develop such a prognostic imaging tool because they bind to AF-1 (22–24) that is common to both full-length AR and AR-Vs. EPI-001 and its stereoisomers (e.g., EPI-002) and analogs (e.g., EPI-506) were developed as AF-1 inhibitors to block transactivation of both full-length AR and AR-Vs. EPI-506 received investigational new drug approval from the FDA and Health Canada (i.e., acceptable safety profile at therapeutic doses) and is currently in clinical trials in the US and Canada for CRPC patients that have failed abiraterone and/or enzalutamide.…”

Section: Introductionmentioning

confidence: 99%

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An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

et al. 2016

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Constitutively active splice variants of androgen receptor (AR-Vs) lacking ligand-binding domain (LBD) are a mechanism of resistance to androgen receptor LBD–targeted (AR LBD–targeted) therapies for metastatic castration-resistant prostate cancer (CRPC). There is a strong unmet clinical need to identify prostate cancer patients with AR-V–positive lesions to determine whether they will benefit from further AR LBD–targeting therapies or should receive taxanes or investigational drugs like EPI-506 or galeterone. Both EPI-506 (NCT02606123) and galeterone (NCT02438007) are in clinical trials and are proposed to have efficacy against lesions that are positive for AR-Vs. AR activation function-1 (AF-1) is common to the N-terminal domains of full-length AR and AR-Vs. Here, we provide proof of concept for developing imaging compounds that directly bind AR AF-1 to detect both AR-Vs and full-length AR. 123I-EPI-002 had specific binding to AR AF-1, which enabled direct visualization of CRPC xenografts that express full-length AR and AR-Vs. Our findings highlight the potential of 123I-EPI-002 as an imaging agent for the detection of full-length AR and AR-Vs in CRPC.

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Section: Resultssupporting

confidence: 84%

“…EPI-002 and analogs bind to AR AF-1 (22, 23) and specifically to Tau-5 in the AF-1 region (24). Here, we show that 123 I-EPI-002 binds to recombinant full-length AR (Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

et al. 2016

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“…EPI-001) (Myung, et al 2013). EPI-001 binds to the AF1 domain of the AR, preventing AR transactivation (Andersen, et al 2010; De Mol, et al 2016; Myung et al 2013). Furthermore, it induced regression of CRPC xenografts in nude mice with little toxicity effects (Andersen et al 2010).…”

Section: Types Of Androgen Deprivation Therapies Used In the Treatmenmentioning

confidence: 99%

Androgen deprivation and immunotherapy for the treatment of prostate cancer

Gamat¹,

McNeel²

2017

Endocrine-Related Cancer

111

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Prostate cancer is the most common newly diagnosed malignancy in men, and the second most common cause of cancer-related death in the United States. The primary treatment for recurrent prostate cancer is androgen deprivation, and this therapy is typically continued life-long for patients with metastatic prostate cancer. Androgens and androgen deprivation have profound effects on the immune system, a finding that has become more appreciated in an era where immune-based treatments for cancer are being increasingly explored. Preclinical studies suggest that androgen deprivation could potentially positively or negatively affect the use of approved immunotherapies, or those that are being developed for the treatment of prostate cancer. In this review, we provide a brief overview of the different types of androgen deprivation treatments used in the management of prostate cancer, discuss their effects on prostate tumors and the immune system, and how they are being explored in combination with immunotherapy. Finally, we address some of the critical questions in the field that must be answered to identify the best approaches to combine androgen deprivation with immunotherapy for the treatment of prostate cancer.

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“…Despite the intrinsically disordered nature of the AR-NTD, which has greatly hindered its structural characterization, agents targeting this domain have also been developed. EPI-001 interacts with and covalently binds to the TAU5 domain in the AF-1 region of the AR-NTD (De Mol et al 2016), thereby inhibiting AR:coactivator interactions (e.g. CBP and RAP74) and attenuating AR and AR-V transcriptional activity (Andersen et al 2010, Myung et al 2013.…”

Section: Targeting Dna Binding and N-terminal Functions Of Armentioning

confidence: 99%

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

Coutinho¹,

Day²,

Tilley³

et al. 2016

Endocrine-Related Cancer

150

122

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The androgen receptor (AR) signaling axis drives all stages of prostate cancer, including the lethal, drug-resistant form of the disease termed castration-resistant prostate cancer (CRPC), which arises after failure of androgen deprivation therapy (ADT). Persistent AR activity in spite of ADT and the second-generation AR-targeting agents enzalutamide and abiraterone is achieved in many cases by direct alterations to the AR signaling axis. Herein, we provide a detailed description of how such alterations contribute to the development and progression of CRPC. Aspects of this broad and ever-evolving field specifically addressed in this review include: the etiology and significance of increased AR expression; the frequency and role of gain-of-function mutations in the AR gene; the function of constitutively active, truncated forms of the AR termed AR variants and the clinical relevance of alterations to the activity and expression of AR coregulators. Additionally, we examine the novel therapeutic strategies to inhibit these classes of therapy resistance mechanisms, with an emphasis on emerging agents that act in a manner distinct from the current ligand-centric approaches. Throughout, we discuss how the central role of AR in prostate cancer and the constant evolution of the AR signaling axis during disease progression represent archetypes of two key concepts in oncology, oncogene addiction and therapy-mediated selection pressure.

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EPI-001, A Compound Active against Castration-Resistant Prostate Cancer, Targets Transactivation Unit 5 of the Androgen Receptor

Cited by 115 publications

References 39 publications

An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

An imaging agent to detect androgen receptor and its active splice variants in prostate cancer

Androgen deprivation and immunotherapy for the treatment of prostate cancer

Androgen receptor signaling in castration-resistant prostate cancer: a lesson in persistence

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