Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model

Bruno, Robert D.; Vasaitis, Tadas S.; Gediya, Lalji K.; Purushottamachar, Puranik; Godbole, Abhijit M.; Ateş‐Alagöz, Zeynep; Brodie, Angela; Njar, Vincent C.O.

doi:10.1016/j.steroids.2011.06.002

Cited by 70 publications

(62 citation statements)

References 35 publications

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“…TAK700, a non-steroidal CYP17A1 inhibitor, is an example of more selective CYP17A1 inhibitor; however, the phase 3 clinical trial with TAK700 has ended preliminary because of the observation that TAK700 plus prednisone would not likely meet the primary endpoint of improved overall survival compared with placebo plus prednisone. For TOK-001, it is known that it is not only a CYP17 inhibitor, but also a competitive AR antagonist that results in the downregulation of the AR (Vasaitis et al 2008, Bruno et al 2011). …”

Section: Figurementioning

confidence: 99%

Androgen receptor antagonists for prostate cancer therapy

Helsen¹,

Broeck²,

Voet³

et al. 2014

Endocrine-Related Cancer

123

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Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

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Section: Figurementioning

confidence: 99%

Androgen receptor antagonists for prostate cancer therapy

Helsen¹,

Broeck²,

Voet³

et al. 2014

Endocrine-Related Cancer

123

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“…As mentioned above, the CYP17A1 inhibitor galeterone not only inhibits the enzyme but is also a competitive AR antagonist and causes degradation of the AR and its variants AR-V7 and Arv567es [153,[166][167][168] . Furthermore, galeterone also impaired AR binding to DNA and selectively up-regulated degradation of the mutated T878A AR protein [122,123] .…”

Section: Bifunctional Inhibitors and Antagonists Targeting The Ar Axismentioning

confidence: 98%

Androgen-AR axis in primary and metastatic prostate cancer: chasing steroidogenic enzymes for therapeutic intervention

Pippione¹,

Boschi²,

Pors³

et al. 2017

JCMT

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Androgens play an important role in prostate cancer (PCa) development and progression. Although androgen deprivation therapy remains the front-line treatment for advanced prostate cancer, patients eventually relapse with the lethal form of the disease. The prostate tumor microenvironment is characterised by elevated tissue androgens that are capable of activating the androgen receptor (AR). Inhibiting the steroidogenic enzymes that play vital roles in the biosynthesis of testosterone (T) and dihydrotestosterone (DHT) seems to be an attractive strategy for PCa therapies. Emerging data suggest a role for the enzymes mediating pre-receptor control of T and DHT biosynthesis by alternative pathways in controlling intratumoral androgen levels, and thereby influencing PCa progression. This supports the idea for the development of multi-targeting strategies, involving both dual and multiple inhibitors of androgen-metabolising enzymes that are able to affect androgen synthesis and signalling at different points in the biosynthesis. In this review, we will focus on CYP17A1, AKR1C3, HSD17B3 and SRD5A, as these enzymes play essential roles in all the three androgenic pathways. We will review also the AR as an additional target for the design of bifunctional drugs. Targeting intracrine androgens and AKR1C3 have potential to overcome enzalutamide and abiraterone resistance and improve survival of advanced prostate cancer patients.

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“…Finalmente, la maximización de la terapia con un fármaco que combine la inhibición enzimática CYP-17 y del RA es la lógica detrás del desarrollo de TOK-001 46 , actualmente en fases iniciales de evaluación 47 .…”

Section: Otras Terapias Hormonalesunclassified