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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Galeterone (also known as TOK-001 or VN/124-1) is a novel SAA developed by Tokai Pharmaceuticals for the treatment of prostate cancer (Figure 8.40). It has a similar structure to abiraterone, differing only in replacement of the 3-pyridyl ring at the C17-position with an N-linked benzo[d]imidazole moiety, and removal of the acetyl group at the C3-position (a transformation that occurs in the metabolism of abiraterone). Structures of the experimental anti-androgen agents galeterone (TOK-001 or VN/124-1) and orteronel (TAK-700).
CTC-derived AR-V7 detection as a prognostic and predictive biomarker in advanced prostate cancer
Published in Expert Review of Molecular Diagnostics, 2018
Diogo A. Bastos, Emmanuel S. Antonarakis
The first large prospective randomized trial to demonstrate the prognostic significance of AR-V7 status in mCRPC was the ARMOR3-SV trial, which compared galeterone vs. enzalutamide in patients with CTC-based AR-V7(+) disease who had not previously received ARS inhibitors or taxane agents [58]. Galeterone is a selective multitargeted molecule that acts as a CYP17 inhibitor, AR antagonist, and degrader (including AR-V7 degrader), with potential activity in AR-V7(+) patients based on initial preclinical and initial clinical studies [59]. The AR-V7 biomarker test used for eligibility assessment was a derivation of the mRNA-based RT-PCR assay first reported by the Johns Hopkins group [37]. Of the 953 patients screened using this assay, only 8% (73) were AR-V7(+) and 38 patients were randomized to enzalutamide or galeterone. In this trial, AR-V7 detection was associated with worse prognostic features, including higher baseline PSA levels, more bone lesions, higher ECOG perfrmance status (PS) status, and prior antiandrogen and docetaxel use compared to patients with no CTC detected or AR-V7(−) CTCs [58]. Because 7 of the first 12 treated AR-V7(+) patients developed rapid disease progression (early censoring rate of 58%), the data and safety monitoring committee recommended premature termination of the study since it was unlikely to meet its primary end point. As a result of this early trial closure, galeterone is no longer being developed as a prostate cancer therapeutic.
Perspectives on the current and emerging chemical androgen receptor antagonists for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2019
Athanasios E. Dellis, Athanasios G. Papatsoris
Galeterone (TOK-001), or 3β-hydroxy-17-(1H-benzimidazole-1-yl) androsta-5,16-diene, is a 17-heteroazole steroidal analogue (initially designated as VN/124–1) [67]. Galeterone was originally designed as a CYP17A1 inhibitor, and further found to be a potent AR antagonist, effectively preventing the binding of synthetic androgens to mutant and wild-type AR and finally increasing AR degradation [68]. Furthermore, it was demonstrated that galeterone functioned as a direct AR competitive antagonist, acting similarly to enzalutamide [69]. In the ARMOR (androgen receptor modulation optimized for response) study, a phase 1 multicenter, open-label, dose-escalation clinical trial, galeterone showed a very good safety profile and it was well tolerated with a low grade of adverse events. PSA halving reductions were more than 20%, while there was further oncological improvement confirmed radiographically. Based on these promising results, galeterone received the fast track designation from the Food and Drug Administration (FDA) for the treatment of CRPC. ARMOR2 was a multicenter two-part phase 2 study [70], where galeterone was re-formulated into a spray-dried dispersion with improved oral bioavailability and favorable PK and was proven to be well tolerated with low-grade reversible adverse effects. Galeterone was further compared to ENZ in a phase 3 clinical trial (ARMOR3-SV) for AR-V7-expressing mCRPC. However, on the 26th of July 2016, after a data monitoring committee determined that the trial was unlikely to meet its endpoint, the discontinuation of ARMOR3-SV was announced [71] and one year later the development of galeterone was discontinued [72].
New benzothieno[2,3-c]pyridines as non-steroidal CYP17 inhibitors: design, synthesis, anticancer screening, apoptosis induction, and in silico ADME profile studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Nadia A. Khalil, Eman M. Ahmed, Ashraf F. Zaher, Eman A. Sobh, Samiha A. El-Sebaey, Mona S. El-Zoghbi
Several categories of steroidal and non-steroidal CYP17 inhibitors were developed and characterised as an effective treatment of advanced prostate cancer cases18. Such include abiraterone acetate I, a steroidal antiandrogen prodrug, which was described for the treatment of metastatic castration-resistant prostate cancer (mCRPC)19, however, it showed undesirable side effects as a result of its non-selectivity. The solution to this problem came in the concomitant administration of prednisone. Galeterone II is an investigational steroidal antiandrogen drug used for the treatment of mCRPC cases that acts by a dual mechanism20. The first involves AR antagonism, thereby preventing the testosterone from binding to its receptor, while the second mechanism is inhibition of CYP17 that reduces the synthesis of androgens, being more specific to 17α-lyase than 17α-hydrolyase21. CFG920 III is a new CYP17 inhibitor in phase I clinical trial used in CRPC patients who are abiraterone resistant22. A very recent drug approved by FDA in 2018 is apalutamide IV, to be used for advanced prostate cancer cases by preventing testosterone hormone from binding to androgen receptor23. Compounds Va–e bearing various bicyclic fused ring systems were reported to have potent CYP17 inhibitory activity with IC50 values ranging from 16–95 nM, except Vc displayed moderate inhibition. The most promising scaffold was Ve with a benzothiophene core in both vitro and vivo evaluation24. The selective CYP17 inhibitors include YM116 VI, which has a tricyclic fused ring system, which showed a loss in rat prostatic weight by reducing androgen production in the testes and adrenal glands25. Literature survey on non-steroidal prostate cancer inhibitors demonstrated that the tetrahydrobenzo[4,5]thieno[2,3-c]pyridine derivatives, VIIa–d, exhibited a comparable potency to abiraterone in inhibiting rat CYP17 enzyme and were able to decrease plasma testosterone level in a dose-dependent manner26 (Figure 1).