Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Norris, John D.; Ellison, Stephanie J.; Baker, Jennifer G.; Stagg, David B.; Wardell, Suzanne E.; Park, Sunghee; Alley, Holly M.; Baldi, Robert; Yllanes, Alexander P.; Andreano, Kaitlyn J.; Stice, James P.; Lawrence, Scott A.; Eisner, Joel R.; Price, Douglas K.; Moore, William R.; Figg, William D.; McDonnell, Donald P.

doi:10.1172/jci87328

Cited by 44 publications

(38 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…While nominally a blocker of androgen biosynthesis from adrenal precursors, Abiraterone, and particularly its oxidized metabolite D4A, are also direct AR antagonist ligands. 118,119 Abiraterone therapy also elevates levels of progestational ligands and suppresses corticosteroid production, necessitating corticosteroid supplementation. These three mutations reduce AR binding specificity and are activated by progestins and corticosteroids.…”

Section: Figurementioning

confidence: 99%

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

et al. 2018

View full text Add to dashboard Cite

Estrogen receptor alpha (ERα), a key driver of breast cancer, normally requires estrogen for activation. Mutations that constitutively activate ERα without the need for hormone are frequently found in endocrine therapy-resistant breast cancer metastases and are associated with poor patient outcomes. The location of these mutations in the ER ligand-binding domain and their impact on receptor conformation suggest that they subvert distinct mechanisms that normally maintain the low basal state of wild-type ERα in the absence of hormone. Such mutations provide opportunities to probe fundamental issues underlying ligand-mediated control of ERα activity. Instructive contrasts between these ER mutations and those that arise in androgen receptor (AR) during antiandrogen treatment of prostate cancer highlight differences in how activating functions in ER vs. AR control receptor activity, how hormonal pressures (deprivation vs. antagonism) drive the selection of phenotypically different mutants, and how altered protein conformations can reduce antagonist potency and altered ligand-receptor contacts can invert the response that a receptor has to an agonist vs. an antagonist. A deeper understanding of how ligand regulation of receptor conformation is linked to receptor function offers a conceptual framework for developing new antiestrogens that might be more effective in preventing and treating breast cancer.

show abstract

Section: Figurementioning

confidence: 99%

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

et al. 2018

View full text Add to dashboard Cite

show abstract

“…its mechanism of clinical activity is complicated by its inhibition of the androgen receptor and by the activities of metabolites (65,66).…”

Section: Editors' Pick: P450 17a1 Substrate Bindingmentioning

confidence: 99%

Conformational selection dominates binding of steroids to human cytochrome P450 17A1

Guengerich

Wilkey

Glass

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Ruma Banerjee Cytochrome P450 (P450, CYP) enzymes are the major catalysts involved in the oxidation of steroids as well as many other compounds. Their versatility has been explained in part by flexibility of the proteins and complexity of the binding mechanisms. However, whether these proteins bind their substrates via induced fit or conformational selection is not understood. P450 17A1 has a major role in steroidogenesis, catalyzing the two-step oxidations of progesterone and pregnenolone to androstenedione and dehydroepiandrosterone, respectively, via 17␣-hydroxy (OH) intermediates. We examined the interaction of P450 17A1 with its steroid substrates by analyzing progress curves (UV-visible spectroscopy), revealing that the rates of binding of any of these substrates decreased with increasing substrate concentration, a hallmark of conformational selection. Further, when the concentration of 17␣-OH pregnenolone was held constant and the P450 concentration increased, the binding rate increased, and such opposite patterns are also diagnostic of conformational selection. Kinetic simulation modeling was also more consistent with conformational selection than with an induced-fit mechanism. Cytochrome b 5 partially enhances P450 17A1 lyase activity by altering the P450 17A1 conformation but did not measurably alter the binding of 17␣-OH pregnenolone or 17␣-OH progesterone, as judged by the apparent K d and binding kinetics. The P450 17A1 inhibitor abiraterone also bound to P450 17A1 in a multistep manner, and modeling indicated that the selective inhibition of the two P450 17A1 steps by the drug orteronel can be rationalized only by a multiple-conformation model. In conclusion, P450 17A1 binds its steroid substrates via conformational selection. Cytochrome P450 (P450) 2 enzymes are the main catalysts involved in the oxidation of steroids, drugs, fat-soluble vitamins, chemical carcinogens, and many other chemicals (1, 2). Collectively, they account for Ͼ95% of the oxidations and This work was supported by National Institutes of Health Grants R01 GM118122 (to F. P. G.) and T32 ES007028 (to F. P. G., support of S. M. G. and M. J. R.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This article was selected as one of our Editors' Picks. This article contains Scheme S1 and Figs. S1-S8.

show abstract

“…Seviteronel has an approximately 10-fold selectivity toward CYP17 lyase over hydroxylase (16) and is a competitive antagonist of both wild-type and mutated forms of the AR (e.g., T877A and F876L; ref. 17). With regards to enzalutamide-resistant cell-line growth, C4-2, C4-2B, MR49C, and MR49F, seviteronel was a more potent inhibitor than AA (18,19).…”

Section: Introductionmentioning

confidence: 94%

“…With regards to enzalutamide-resistant cell-line growth, C4-2, C4-2B, MR49C, and MR49F, seviteronel was a more potent inhibitor than AA (18,19). In vivo, seviteronel inhibits the growth of multiple CRPC cell lines, including MR49F, MDA-PCA-133, and LNCaP (17,19,20).…”

Section: Introductionmentioning

confidence: 96%

Phase I Study of Seviteronel, a Selective CYP17 Lyase and Androgen Receptor Inhibitor, in Men with Castration-Resistant Prostate Cancer

Gupta

Nordquist

Fleming

et al. 2018

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Seviteronel (INO-464) is a selective cytochrome P450c17a (CYP17) 17,20-lyase (lyase) and androgen receptor (AR) inhibitor with antitumor activity and This open-label phase I clinical study evaluated the safety, tolerability, pharmacokinetics and activity of once-daily seviteronel in male chemotherapy-naïve subjects with castration-resistant prostate cancer (CRPC). Seviteronel was administered at 600 mg once daily with dose titration (DT) and in modified 3 + 3 dose escalation once-daily cohorts at 600, 750, and 900 mg without DT. The primary objectives of this study were to establish safety, tolerability, and the MTD of seviteronel in chemotherapy-naïve subjects with or without prior treatment with FDA-approved CRPC treatments, abiraterone acetate (AA), and enzalutamide. Secondary objectives were to assess pharmacokinetics, PSA, tumor response, and endocrine results. Twenty-one subjects were enrolled. No dose-limiting toxicities (DLT) were observed through 750 mg once daily. Most treatment-emergent adverse events (AE) reported at grade 1-2. The most commonly reported AEs were fatigue (71%), dizziness (52%), blurred vision (38%), and dysgeusia (33%), with most AEs improving after dose reduction or dose interruption. Once-daily seviteronel was generally well tolerated in this phase I study of men with CRPC, a majority of which had progressed on prior AA or enzalutamide, or both. Of the doses evaluated, 600 mg once daily was chosen as the recommended phase II dose for future studies in subjects with CRPC. .

show abstract

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Cited by 44 publications

References 58 publications

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance

Conformational selection dominates binding of steroids to human cytochrome P450 17A1

Phase I Study of Seviteronel, a Selective CYP17 Lyase and Androgen Receptor Inhibitor, in Men with Castration-Resistant Prostate Cancer

Contact Info

Product

Resources

About