Delving into the Latest Updates on Galeterone with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Galeterone (USAN)

+ [3]

Target

AR x CYP17A1

Mechanism

AR antagonists(Androgen Receptor antagonists), CYP17A1 inhibitors(Steroid 17-alpha-hydroxylase inhibitors)

Therapeutic Areas

NeoplasmsUrogenital Diseases

Active Indication

Prostatic Cancer

Inactive Indication

Metastatic castration-resistant prostate cancer

Originator Organization

TOKAI RIKA CO., LTD.

Active Organization

TOKAI RIKA CO., LTD.

Inactive Organization

LTN Pharmaceuticals, Inc.

Educational + Scientific Products Ltd.

Eledon Pharmaceuticals, Inc.

Drug Highest PhasePhase 3

First Approval Date-

Regulation-

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Structure

Molecular FormulaC26H32N2O

InChIKeyPAFKTGFSEFKSQG-PAASFTFBSA-N

CAS Registry851983-85-2

There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.

01 Oct 2023·Bioorganic Chemistry

Salinization Dramatically Enhance the Anti-Prostate Cancer Efficacies of AR/AR-V7 and Mnk1/2 Molecular Glue Degraders, Galeterone and VNPP433-3β Which Outperform Docetaxel and Enzalutamide in CRPC CWR22Rv1 Xenograft Mouse Model

Article

Author: Thankan, Retheesh S ; Weber, David J ; Thomas, Elizabeth ; Purushottamachar, Puranik ; Njar, Vincent C O

Galeterone, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Gal, 1) and VNPP433-3β, 3β-(1H-imidazole-1-yl-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (2) are potent molecular glue degrader modulators of AR/AR-V7 and Mnk1/2-eIF4E signaling pathways, and are promising Phase 3 and Phase 1 drug candidates, respectively. Because appropriate salts can be utilized to create new chemical entities with enhanced aqueous solubility, in vivo pharmacokinetics, and enhanced in vitro and in vivo efficacies, the monohydrochloride salt of Gal (3) and the mono- and di-hydrochlorides salts of compound 2, compounds 4 and 5, respectively, were synthesized. The salts were characterized using ¹H NMR, ¹³C NMR and HRMS analyses. Compound 3 displayed enhanced in vitro antiproliferative activity (7.4-fold) against three prostate cancer cell lines but surprisingly decreased plasma exposure in the pharmacokinetics study. The antiproliferative activities of the compound 2 salts (4 and 5) were equivalent to that of compound 2, but their oral pharmacokinetic profiles were significantly enhanced. Finally, and most importantly, oral administration of the parent compounds (1 and 2) and their corresponding salts (3, 4 and 5) caused dose-dependent potent inhibition/regression of aggressive and difficult-to-treat CWR22Rv1 tumor xenografts growth, with no apparent host toxicities and were highly more efficacious than the blockbuster FDA-approved prostate cancer drugs, Enzalutamide (Xtandi) and Docetaxel (Taxotere). Thus, the HCl salts of Gal (3) and VNPP433-3β (4 and 5) are excellent orally bioavailable candidates for clinical development.

21 Jun 2023·AAPS PharmSciTech

Can the Oral Bioavailability of the Discontinued Prostate Cancer Drug Galeterone Be Improved by Processing Method? KinetiSol® Outperforms Spray Drying in a Head-to-head Comparison.

Article

Author: Kucera, Sandra ; Thompson, Stephen A ; Miller, Dave ; Williams, Robert O ; Davis, Daniel A ; Gala, Urvi

Galeterone, a novel prostate cancer candidate treatment, was discontinued after a Phase III clinical trial due to lack of efficacy. Galeterone is weakly basic and exhibits low solubility in biorelevant media (i.e., ~ 2 µg/mL in fasted simulated intestinal fluid). It was formulated as a 50-50 (w/w) galeterone-hypromellose acetate succinate spray-dried dispersion to increase its bioavailability. Despite this increase, the bioavailability of this formulation may have been insufficient and contributed to its clinical failure. We hypothesized that reformulating galeterone as an amorphous solid dispersion by KinetiSol® compounding could increase its bioavailability. In this study, we examined the effects of composition and manufacturing technology (Kinetisol and spray drying) on the performance of galeterone amorphous solid dispersions. KinetiSol compounding was utilized to create galeterone amorphous solid dispersions containing the complexing agent hydroxypropyl-β-cyclodextrin or hypromellose acetate succinate with lower drug loads that both achieved a ~ 6 × increase in dissolution performance versus the 50-50 spray-dried dispersion. When compared to a spray-dried dispersion with an equivalent drug load, the KinetiSol amorphous solid dispersions formulations exhibited ~ 2 × exposure in an in vivo rat study. Acid-base surface energy analysis showed that the equivalent composition of the KinetiSol amorphous solid dispersion formulation better protected the weakly basic galeterone from premature dissolution in acidic media and thereby reduced precipitation, inhibited recrystallization, and extended the extent of supersaturation during transit into neutral intestinal media.

100 Deals associated with Galeterone

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External Link

KEGG	Wiki	ATC	Drug Bank
D10125	Galeterone	-	DB12415

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Prostatic Cancer	Phase 3	-	TOKAI RIKA CO., LTD.	-
Metastatic castration-resistant prostate cancer	Discovery	BE	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Discovery	GB	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Discovery	CA	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Discovery	IT	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Discovery	FR	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Discovery	US	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Discovery	ES	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Discovery	AU	LTN Pharmaceuticals, Inc.	01 Jun 2015

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02438007 (ARMOR3-SV, Pubmed) Manual	Phase 3	Metastatic castration-resistant prostate cancer First line	38	Galeterone	(cvuderehzf) = msbmhlfcaz udblzlczcv (fvfcshutae )	Negative	01 Dec 2019
				Enzalutamide	(cvuderehzf) = fqqnmoctzv udblzlczcv (fvfcshutae )
NCT02438007 (ARMOR3-SV, ASCO2017)	Phase 3	Metastatic castration-resistant prostate cancer	953	Galeterone	tnfphxxlob(zzigsexmhu) = fjhrbzjdsz jlpazsnvyt (qhniyqasvh )	Negative	30 May 2017
				Enzalutamide	tnfphxxlob(zzigsexmhu) = wxuroecqgl jlpazsnvyt (qhniyqasvh )
ARMOR3-SV (ASCO2016)	Phase 3	AR-V7 positive Castration-Resistant Prostatic Cancer	-	Galeterone	hsklkarevl(vlaxnsnspo) = ylfaegpclh jvyehyhdbw (okgzhqgkbx )	-	20 May 2016
NCT00959959 (ARMOR1 \| ARMOR2 part 1, Pubmed \| Clin Cancer Res) Manual	Phase 1/2	Castration-Resistant Prostatic Cancer	77	Galeterone (ARMOR1)	(opjwkauahw) = the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. aqdmkvkxlv (bjxazfgwda )	Positive	15 Mar 2016
				Galeterone (ARMOR2)