Description
Galeterone (TOK-001) is a small molecule oral drug that disrupts AR signaling by a novel triple mechanism: it potently and selectively inhibits CYP17 lyase, potently antagonizes AR and decreases AR protein levels (wild-type and mutant), leading to antitumor activity. Galeterone has shown significant anti-tumour activity with a well-tolerated safety profile in patients with CRPC in phase I and II clinical studies.
Uses
Galeterone is an androgen receptor antagonist and CYP17A1 enzyme inhibitor. It has been used in trials studying the treatment of Prostate Cancer.
Definition
ChEBI: Galeterone is a 3-hydroxy steroid. It has a role as an androgen.
Biological Activity
The cytochrome P450 (CYP) isoform CYP17 is also known as steroid 17α-hydroxylase/17,20 lyase because it catalyzes both 17α-hydroxylase and 17,20 lyase reactions in the synthesis of steroids, including androgens, estrogens, glucocorticoids, and mineralocorticoids. Galeterone is a CYP17 inhibitor (IC50 = 300 nM) that has been shown to competitively block synthetic androgen binding (EC50 = 845 nM) and to antagonize the androgen receptor in transcriptional activation assays. Galeterone can inhibit the growth of castration-resistant prostate cancer cells with an IC50 value of 2.9 μM and demonstrates synergy with everolimus or gefitinib for growth inhibition.
Synthesis
GENERAL STEPS: (3BETA)-17-(1H-benzimidazol-1-yl)androsta-5,16-dien-3-ol 3-acetate (1.3 g, 3.02 mmol) was dissolved in methanol (20 mL) under an inert argon (Ar) atmosphere. To the resulting solution was added 10% potassium methanol (KOH) solution (8 mL). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was subsequently concentrated under reduced pressure to a volume of about 10 mL at about 40 °C. The concentrated solution was poured into ice water (300 mL), and the precipitated white precipitate was filtered, washed with water and dried. The target product (3β-hydroxy-17-(1H-benzimidazol-1-yl)androsta-5,16-diene) was obtained by solvent recrystallization over a mixture of ethyl acetate (EtOAc)/methanol (MeOH) (1.10 g, 94% yield), melting point 189-190 °C. Infrared spectra (CHCl3) showed absorption peaks located at 2934, 2339, 1609, 1490, 1453, 1291, 1040, 837, 808, 705, 663, 608, 578, 550, 517 cm-1 .1H NMR (300 MHz, CDCl3) δ 1.02 (s, 3H, 18-CH3) 1.07 (s, 3H, 19-CH3), 3.55 (m, 1H, 3α-H), 5.41 (br s, 1H, 6-H), 5.99 (s, 1H, 16-H), 7.30 (m, 2H, aromatic-H), 7.54 (s, 1H, aromatic-H), 7.80 (s, 1H, aromatic-H), 7.96 (s, 1H, 2X-H). . The calculated value of high resolution mass spectrometry (HRMS) was 411.2407 (C26H32ON2-Na+) and the measured value was 411.2396.
Mode of action
Galeterone is an orally bioavailable small-molecule androgen receptor modulator and CYP17 lyase inhibitor with potential antiandrogen activity. Galeterone exhibits three distinct mechanisms of action: 1) as an androgen receptor antagonist, 2) as a CYP17 lyase inhibitor and 3) by decreasing overall androgen receptor levels in prostate cancer tumors, all of which may result in a decrease in androgen-dependent growth signaling. Localized to the endoplasmic reticulum (ER), the cytochrome P450 enzyme CYP17 (P450C17 or CYP17A1) exhibits both 17alpha-hydroxylase and 17,20-lyase activities, and plays a key role in the steroidogenic pathway that produces progestins, mineralocorticoids, glucocorticoids, androgens, and estrogens.
References
[1]. devore n m, & scott e e. structures of cytochrome p450 17a1 with prostate cancer drugs abiraterone and tok-001. nature, 2012, 482: 116-119.
[2]. mallik i, davila m, tapia t, et al. androgen regulates cdc6 transcription through interactions between androgen receptor and e2f transcription factor in prostate cancer cells. biochimica et biophysica acta (bba) - molecular cell research, 2008,1783:1737-1744.
[3]. bruno r d, vasaitis t s, gediya l. k, et al. synthesis and biological evaluations of putative metabolically stable analogs of vn/124-1 (tok-001): head to head anti-tumor efficacy evaluation of vn/124-1 (tok-001) and abiraterone in lapc-4 human prostate cancer xenograft model. steroids, 2011,76: 1268-1279.
