Systematic Structure Modifications of Multitarget Prostate Cancer Drug Candidate Galeterone To Produce Novel Androgen Receptor Down-Regulating Agents as an Approach to Treatment of Advanced Prostate Cancer

Purushottamachar, Puranik; Godbole, Abhijit M.; Gediya, Lalji K.; Martin, Marlena S.; Vasaitis, Tadas S.; Kwegyir-Afful, Andrew K.; Ramalingam, Senthilmurugan; Ateş‐Alagöz, Zeynep; Njar, Vincent C.O.

doi:10.1021/jm400048v

Cited by 99 publications

(96 citation statements)

References 75 publications

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“…1c). The calculated IC50 for LNCaP cells (5.6±0.8 µM; n=4) was comparable to that published by other authors using end-point cytotoxicity assays (between 1 and 5 µM) 9,10 . In contrast, the calculated IC50 value for PC-3 cells had to be extrapolated up to a non-physiological value (34.9±9 µM; n=4).…”

Section: Estimation Of Enzalutamide Ic50s On Two Human Metastatic Prosupporting

confidence: 86%

Radiopotentiation of Enzalutamide Over Human Prostate Cancer Cells as Assessed by Real-Time Cell Monitoring

Barrado¹,

Blanco‐Luquin²,

Andrea-Navarrete³

et al. 2018

Preprint

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While radiotherapy is the first line of treatment for prostate cancer, androgen blockade therapies are demonstrating significant survival benefit as monotherapies. As androgen blockade can cause cell death by apoptosis, it is likely that androgen blockade will potentiate the cytotoxic activities of radiotherapy. Here we tested the potential synergistic effects of these two treatments over two human metastatic prostate cancer cells by real time growth monitoring (RTCA), androgen-sensitive LNCaP cells and androgen-resistant PC-3. Both cell lines were highly resistant to high doses of radiotherapy. A pre-treatment of LNCaP cells with IC50 concentrations of enzalutamide significantly sensitized them to radiotherapy through enhanced apoptosis. In contrast, enzalutamide resistant PC-3 cells were not sensitized to radiotherapy by androgen blockade. These results provide evidence that the enzalutamide/radiotherapy combination could maximize therapeutic responses in patients with enzalutamide-sensitive prostate cancer.

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Section: Estimation Of Enzalutamide Ic50s On Two Human Metastatic Prosupporting

confidence: 86%

Radiopotentiation of Enzalutamide Over Human Prostate Cancer Cells as Assessed by Real-Time Cell Monitoring

Barrado¹,

Blanco‐Luquin²,

Andrea-Navarrete³

et al. 2018

Preprint

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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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“…Preclinical in vitro and in vivo data have shown that galeterone treatment in prostate cancer models resulted in a significant reduction in both full-length AR and AR-V7 splice variant levels. In addition, galeterone has been shown to have activity against AR point mutations T878A (20)(21)(22)(23)(24)(25) and, in preliminary findings, to have activity in cells expressing the AR point mutation F876L (27).…”

Section: Introductionmentioning

confidence: 97%

“…Preclinical data have shown that galeterone is a selective potent CYP17 inhibitor and a potent AR antagonist, but unlike other available agents that target androgen signaling, galeterone reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation (20)(21)(22)(23)(24)(25)(26). Preclinical in vitro and in vivo data have shown that galeterone treatment in prostate cancer models resulted in a significant reduction in both full-length AR and AR-V7 splice variant levels.…”

Section: Introductionmentioning

confidence: 99%

Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer

Montgomery

Eisenberger

Rettig³

et al. 2016

Clinical Cancer Research

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Purpose: Galeterone is a selective, multitargeted agent that inhibits CYP17, antagonizes the androgen receptor (AR), and reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation. These open-label phase I and II studies [Androgen Receptor Modulation Optimized for Response-1 (ARMOR1) and ARMOR2 part 1] evaluated the efficacy and safety of galeterone in patients with treatment-naive nonmetastatic or metastatic castration-resistant prostate cancer (CRPC) and established a dose for further study.Experimental Design: In ARMOR1, 49 patients received increasing doses (650-2,600 mg) of galeterone in capsule formulation; 28 patients in ARMOR2 part 1 received increasing doses (1,700-3,400 mg) of galeterone in tablet formulation for 12 weeks. Patients were evaluated biweekly for safety and efficacy, and pharmacokinetic parameters were assessed.Results: In ARMOR1, across all doses, 49.0% (24/49) achieved a !30% decline in prostate-specific antigen (PSA; PSA30) and 22.4% (11/49) demonstrated a !50% PSA decline (PSA50). In ARMOR2 part 1, across all doses, PSA30 was 64.0% (16/25) and PSA50 was 48.0% (12/25). In the 2,550-mg dose cohort, PSA30 was 72.7% (8/11) and PSA50 was 54.5% (6/11). Galeterone was well tolerated; the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. Most were mild or moderate in severity and required no action and there were no apparent mineralocorticoid excess (AME) events.Conclusions: The efficacy and safety from ARMOR1 and ARMOR2 part 1 and the pharmacokinetic results support the galeterone tablet dose of 2,550 mg/d for further study. Galeterone was well tolerated and demonstrated pharmacodynamic changes consistent with its selective, multifunctional AR signaling inhibition.

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Systematic Structure Modifications of Multitarget Prostate Cancer Drug Candidate Galeterone To Produce Novel Androgen Receptor Down-Regulating Agents as an Approach to Treatment of Advanced Prostate Cancer

Cited by 99 publications

References 75 publications

Radiopotentiation of Enzalutamide Over Human Prostate Cancer Cells as Assessed by Real-Time Cell Monitoring

Radiopotentiation of Enzalutamide Over Human Prostate Cancer Cells as Assessed by Real-Time Cell Monitoring

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

Androgen Receptor Modulation Optimized for Response (ARMOR) Phase I and II Studies: Galeterone for the Treatment of Castration-Resistant Prostate Cancer

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