Identification of Novel Steroidal Androgen Receptor Degrading Agents Inspired by Galeterone 3β-Imidazole Carbamate

Purushottamachar, Puranik; Kwegyir-Afful, Andrew K.; Martin, Marlena S.; Ramamurthy, Vidya P.; Ramalingam, Senthilmurugan; Njar, Vincent C.O.

doi:10.1021/acsmedchemlett.6b00137

Cited by 20 publications

(23 citation statements)

References 32 publications

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“…The new NGGAs (VNPP414 and VNPP433-3β) were identified from in vitro anti-proliferative activities of our in-house compounds assessed in several PC cell lines, including LNCaP, C4-2B, and CWR22Rv1 (22Rv1) [8]. Because drug resistance remains a major clinical challenge in PC therapy [32,33,34,35,36,37], we compared the efficacies of Gal, VNPP414, and VNPP433-3β against several PC drugs-resistant cell lines, including enzalutamide (MDV-3100)-resistant (MR49F), mitoxantrone-resistant (CWR-R1(MTX), and docetaxel-resistant CWR-R1 (10E) PC cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, we have demonstrated that Gal and the NGGAs target the androgen receptor (including its splice variant AR-V7) and Mnk1/2-eIF4E (eIF4E phosphorylation at serine209) signaling pathways (dual AR/Mnk1/2 inhibitors) and that the NGGAs are more effective than Gal [8,9,11]. Because the androgen receptor is a negative regulator of eIF4E phosphorylation at serine 209 [19,20], our new class of compounds can effectively inhibit Mnk/eIF4E in addition to AR transcriptional activity with the potential to negate negative feedback to prevent PC progression.…”

Section: Discussionmentioning

confidence: 99%

“…In studies designed to enhance the anticancer efficacy of Gal, we discovered potent anti-prostate cancer Gal analogs via structural modification of the C-3 hydroxy group [3,8]. We also discovered that Gal and the next generation Gal analogs (NGGAs), in addition to modulation of AR signaling, also effectively target oncogenic eukaryotic protein translation, via suppression of the cap-dependent protein translational complex, mitogen-activated protein kinase-interacting kinases 1 and 2 (Mnk1/2)-eukaryotic initiation factor 4E (eIF4E) signaling.…”

Section: Introductionmentioning

confidence: 99%

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Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo

Kwegyir-Afful

Ramalingam

Ramamurthy

et al. 2019

Cancers

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These studies compared the efficacies of our clinical agent galeterone (Gal) and the FDA-approved prostate cancer drug, enzalutamide (ENZ) with two lead next generation galeterone analogs (NGGAs), VNPP414 and VNPP433-3β, using prostate cancer (PC) in vitro and in vivo models. Antitumor activities of orally administered agents were also assessed in CWR22Rv1 tumor-bearing mice. We demonstrated that Gal and NGGAs degraded AR/AR-V7 and Mnk1/2; blocked cell cycle progression and proliferation of human PC cells; induced apoptosis; inhibited cell migration, invasion, and putative stem cell markers; and reversed the expression of epithelial-to-mesenchymal transition (EMT). In addition, Gal/NGGAs (alone or in combination) also inhibited the growth of ENZ-, docetaxel-, and mitoxantrone-resistant human PC cell lines. The NGGAs exhibited improved pharmacokinetic profiles over Gal in mice. Importantly, in vivo testing showed that VNPP433-3β (at 7.53-fold lower equimolar dose than Gal) markedly suppressed (84% vs. Gal, 47%; p < 0.01) the growth of castration-resistant PC (CRPC) CWR22Rv1 xenograft tumors, with no apparent host toxicity. ENZ was ineffective in this CRPC xenograft model. In summary, our findings show that targeting AR/AR-V7 and Mnk1/2 for degradation represents an effective therapeutic strategy for PC/CRPC treatment and supports further development of VNPP433-3β towards clinical investigation.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo

Kwegyir-Afful

Ramalingam

Ramamurthy

et al. 2019

Cancers

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“…Galeterone and analogs (VNPT55, VNPP414 and VNPP433-3β) were designed and synthesized in our laboratory [ 26 , 68 , 69 ] and dissolved in DMSO. Gemcitabine was purchased from Sigma Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice

et al. 2016

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Survival rate for pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is poor, with about 80% of patients presenting with the metastatic disease. Gemcitabine, the standard chemotherapeutic agent for locally advanced and metastatic PDAC has limited efficacy, attributed to innate/acquired resistance and activation of pro-survival pathways. The Mnk1/2-eIF4E and NF-κB signaling pathways are implicated in PDAC disease progression/metastasis and also associated with gemcitabine-induced resistance in PDAC. Galeterone (gal), a multi-target, agent in phase III clinical development for prostate cancer has also shown effects on the aforementioned pathways. We show for the first time, that gal/analogs (VNPT55, VNPP414 and VNPP433-3β) profoundly inhibited cell viability of gemcitabine-naive/resistance PDAC cell lines and strongly synergized with gemcitabine in gemcitabine-resistant PDAC cells. In addition, to inducing G1 cell cycle arrest, gal/analogs induced caspase 3-mediated cell-death of PDAC cells. Gal/analogs caused profound downregulation of Mnk1/2, peIF4E and NF-κB (p-p65), metastatic inducing factors (N-cadherin, MMP-1/-2/-9, Slug, Snail and CXCR4) and putative stem cell factors, (β-Catenin, Nanog, BMI-1 and Oct-4). Gal/analog also depleted EZH2 and upregulated E-Cadherin. These effects resulted in significant inhibition of PDAC cell migration, invasion and proliferation. Importantly, we also observed strong MiaPaca-2 tumor xenograft growth inhibition (61% to 92%). Collectively, these promising findings strongly support further development of gal/analogs as novel therapeutics for PDAC.

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“…Also galaterone (3, Figure 4), a known CYP17 inhibitor and AR antagonist, promotes the proteasomal degradation of both AR and its ligand-independent variants AR-V7 and Arv567es [152,153] .…”

Section: Seviteronel (5mentioning

confidence: 99%

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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Identification of Novel Steroidal Androgen Receptor Degrading Agents Inspired by Galeterone 3β-Imidazole Carbamate

Cited by 20 publications

References 32 publications

Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo

Galeterone and The Next Generation Galeterone Analogs, VNPP414 and VNPP433-3β Exert Potent Therapeutic Effects in Castration-/Drug-Resistant Prostate Cancer Preclinical Models In Vitro and In Vivo

Galeterone and its analogs inhibit Mnk-eIF4E axis, synergize with gemcitabine, impede pancreatic cancer cell migration, invasion and proliferation and inhibit tumor growth in mice

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

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