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| Other names | VT-464; INO-464 |
| Routes of administration | By mouth |
| Drug class | Androgen biosynthesis inhibitor;Nonsteroidal antiandrogen |
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| Chemical and physical data | |
| Formula | C18H17F4N3O3 |
| Molar mass | 399.346 g·mol−1 |
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Seviteronel (developmental codesVT-464 and, formerly,INO-464) is anexperimental cancer medication which is under development by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment ofprostate cancer andbreast cancer.[1] It is anonsteroidalCYP17A1 inhibitor and works byinhibiting theproduction ofandrogens andestrogens in the body.[1] As of July 2017, seviteronel is inphase IIclinical trials for both prostate cancer and breast cancer.[1] In January 2016, it was designatedfast-track status by theUnited StatesFood and Drug Administration for prostate cancer.[1][2] In April 2017, seviteronel received fast-track designation for breast cancer as well.[1]
Seviteronel is anonsteroidal antiandrogen, acting specifically as anandrogensynthesisinhibitor via inhibition of theenzymeCYP17A1, for the treatment ofcastration-resistant prostate cancer.[3][4][5][6][7][8] It has approximately 10-foldselectivity for the inhibition of17,20-lyase (IC50Tooltip half-maximal inhibitory concentration = 69 nM) over17α-hydroxylase (IC50 = 670 nM), which results in less interference withcorticosteroid production relative to the approved CYP17A1 inhibitorabiraterone acetate (which must be administered in combination withprednisone to avoidglucocorticoid deficiency andmineralocorticoid excess due to 17α-hydroxylase inhibition) and hence may be administerable without a concomitantexogenousglucocorticoid.[9] Seviteronel is 58-fold more selective for inhibition of 17,20-lyase thanabiraterone (theactive metabolite of abiraterone acetate), which hasIC50 values for inhibition of 17,20-lyase and 17α-hydroxylase of 15 nM and 2.5 nM, respectively.[7] In addition, inin vitro models, seviteronel appears to possess greater efficacy as an antiandrogen relative to abiraterone.[6] Similarly to abiraterone acetate, seviteronel has also been found to act to some extent as anantagonist of theandrogen receptor.[6]
Seviteronel is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name.[10]
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.
