Seviteronel Explained

Seviteronel (developmental codes VT-464 and, formerly, INO-464) is an experimental cancer medication which is under development by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate cancer and breast cancer.[1] It is a nonsteroidal CYP17A1 inhibitor and works by inhibiting the production of androgens and estrogens in the body. As of July 2017, seviteronel is in phase II clinical trials for both prostate cancer and breast cancer. In January 2016, it was designated fast-track status by the United States Food and Drug Administration for prostate cancer.[2] In April 2017, seviteronel received fast-track designation for breast cancer as well.__TOC__

Pharmacology

Pharmacodynamics

Seviteronel is a nonsteroidal antiandrogen, acting specifically as an androgen synthesis inhibitor via inhibition of the enzyme CYP17A1, for the treatment of castration-resistant prostate cancer.[3] [4] [5] [6] [7] [8] It has approximately 10-fold selectivity for the inhibition of 17,20-lyase (= 69 nM) over 17α-hydroxylase (= 670 nM), which results in less interference with corticosteroid production relative to the approved CYP17A1 inhibitor abiraterone acetate (which must be administered in combination with prednisone to avoid glucocorticoid deficiency and mineralocorticoid excess due to 17α-hydroxylase inhibition) and hence may be administerable without a concomitant exogenous glucocorticoid.[9] Seviteronel is 58-fold more selective for inhibition of 17,20-lyase than abiraterone (the active metabolite of abiraterone acetate), which has values for inhibition of 17,20-lyase and 17α-hydroxylase of 15 nM and 2.5 nM, respectively. In addition, in in vitro models, seviteronel appears to possess greater efficacy as an antiandrogen relative to abiraterone. Similarly to abiraterone acetate, seviteronel has also been found to act to some extent as an antagonist of the androgen receptor.

Society and culture

Generic names

Seviteronel is the generic name of the drug and its .[10]

See also

Further reading

External links

Notes and References

  1. Web site: Seviteronel - Innocrin Pharmaceuticals . AdisInsight . Springer Nature Switzerland AG . 2015-07-20 . 2015-07-22 . https://web.archive.org/web/20150722081355/http://adisinsight.springer.com/drugs/800035241 . live .
  2. Web site: FDA grants fast-track status for Innocrin's seviteronel to treat metastatic CRPC. 6 January 2016. PharmaceuticalTechnology. 2 May 2016. 3 June 2016. https://web.archive.org/web/20160603094805/http://www.pharmaceutical-technology.com/news/newsfda-grants-fast-track-status-innocrins-seviteronel-treat-metastatic-crpc-4770025. live.
  3. Yin L, Hu Q, Hartmann RW . Recent progress in pharmaceutical therapies for castration-resistant prostate cancer . International Journal of Molecular Sciences . 14 . 7 . 13958–13978 . July 2013 . 23880851 . 3742227 . 10.3390/ijms140713958 . free .
  4. Stein MN, Patel N, Bershadskiy A, Sokoloff A, Singer EA . Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer . Asian Journal of Andrology . 16 . 3 . 387–400 . 2014 . 24759590 . 4023364 . 10.4103/1008-682X.129133 . free .
  5. Rafferty SW, Eisner JR, Moore WR, Schotzinger RJ, Hoekstra WJ . Highly-selective 4-(1,2,3-triazole)-based P450c17a 17,20-lyase inhibitors . Bioorganic & Medicinal Chemistry Letters . 24 . 11 . 2444–2447 . June 2014 . 24775307 . 10.1016/j.bmcl.2014.04.024 .
  6. Toren PJ, Kim S, Pham S, Mangalji A, Adomat H, Guns ES, Zoubeidi A, Moore W, Gleave ME . 6 . Anticancer activity of a novel selective CYP17A1 inhibitor in preclinical models of castrate-resistant prostate cancer . Molecular Cancer Therapeutics . 14 . 1 . 59–69 . January 2015 . 25351916 . 10.1158/1535-7163.MCT-14-0521 . free .
  7. Book: Hu Q, Hartmann RW . The Renaissance of CYP17 Inhibitors for the Treatment of Prostate Cancer. Neidle S . Cancer Drug Design and Discovery. https://books.google.com/books?id=HS6IAAAAQBAJ&pg=PA342. 30 September 2013. Academic Press. 978-0-12-397228-6. 341–342.
  8. Book: Poole A, Alva A, Batten J, Agarwal N. Metastatic Castrate-Resistant Prostate Inhibitors: Role of Androgen Signaling Inhibitors. Kelly WK, Trabulsi EJ, Zaorsky NG. Prostate Cancer: A Multidisciplinary Approach to Diagnosis and Management. https://books.google.com/books?id=UzTtBQAAQBAJ&pg=PA342. 17 December 2014. Demos Medical Publishing. 978-1-936287-59-8. 342–. 19 October 2016. 10 January 2023. https://web.archive.org/web/20230110003510/https://books.google.com/books?id=UzTtBQAAQBAJ&pg=PA342. live.
  9. Bird IM, Abbott DH . The hunt for a selective 17,20 lyase inhibitor; learning lessons from nature . The Journal of Steroid Biochemistry and Molecular Biology . 163 . 136–146 . October 2016 . 27154414 . 5046225 . 10.1016/j.jsbmb.2016.04.021 . VT464 is another recently developed compound proposed to act as a selective lyase inhibitor, and more complete data is available in the public domain to support this claim. A review of preliminary data released suggest the IC50 for Human CYP17 lyase activity is ten times lower than for hydroxylase 15 and in nonhuman primates VT464 was able to suppress circulating testosterone as effectively as abiraterone, but with minimally depressed cortisol (remaining at 82% control compared to only 9% with aberaterone), and without associated increases in pregnenolone, progesterone and mineralocorticoids otherwise observed with abiraterone. Like Galaterone, VT464 is also in use in clinical trials without co-administration of prednisone. Together with the clear lack of suppression of circulating cortisol in nonhuman primates, these data argue that VT464 may indeed be a selective 17,20 lyase inhibitor. .
  10. International Nonproprietary Names for Pharmaceutical Substances (INN) . WHO Drug Information . 30 . 3 . 2016 . 533 . . https://web.archive.org/web/20220216082642/https://www.who.int/medicines/publications/druginformation/innlists/RL76.pdf . 2022-02-16 .

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