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

Action

antagonists, inhibitors

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/Sequence

Molecular FormulaC26H32N2O

InChIKeyPAFKTGFSEFKSQG-PAASFTFBSA-N

CAS Registry851983-85-2

Herein, we describe a convenient protocol for the synthesis of N-alkenylated heterocycles using abundant ketone electrophiles and T₃P as a water scavenger under microwave irradiation. The method can be applied to a diverse range of NH-heterocycles and ketones with good to excellent yields (up to 94%). This procedure is particularly attractive, as it is metal- and base-free, tolerates a variety of functional groups, and offers ease of product purification. The utility of the protocol was exemplified by synthesizing pharmaceutically relevant scaffolds containing the N-alkenyl motif and was further extended to a one-pot reductive amination sequence.

01 Aug 2024·Biomedicine & Pharmacotherapy

Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation

Article

Author: Njar, Vincent C O ; Meek, Autumn R ; Schormann, Wiebke ; Penn, Linda Z ; Elbaz, Mohamad ; Hamilton, Robert J ; Branchard, Emily ; Dos Santos, Diandra Zipinotti ; Andrews, David W ; Brown, Carla E ; Reed, Mark A

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.

11 Apr 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Structure–Activity Relationship (SAR) Studies of Novel Monovalent AR/AR-V7 Dual Degraders with Potent Efficacy against Advanced Prostate Cancer

Q1 · MEDICINE

Article

Author: Wei, Hanlin ; Hou, Qiangqiang ; Xiang, Hua ; Xiao, Maoxu ; Zhu, Jiacheng ; Tao, Wenxiang ; Fu, Zixuan ; Ha, Si ; Luo, Guoshun

Androgen receptor (AR) has been extensively established as a potential therapeutic target for nearly all stages of prostate cancer (PCa). However, acquired resistance to AR-targeted drugs inevitably develops and severely limits their clinical efficacy. Particularly, there currently exists no efficient treatment for patients expressing the constitutively active AR splice variants, such as AR-V7. Herein, we report the structure-activity relationship studies of 55 N-heterocycle-substituted hydantoins, which identified the structural motifs required for AR/AR-V7 degradation. Among them, the most potent compound 27c exhibited selective AR/AR-V7 degradation over other hormone receptors and excellent antiproliferative activities in LNCaP and 22RV1 cells. RNA sequence analysis confirmed that 27c effectively suppressed transcriptional activity of the AR signaling pathway. Importantly, 27c demonstrated potent antitumor efficacy in an enzalutamide-resistant 22RV1 xenograft model. These results highlight the potential of 27c as a promising dual AR/AR-V7 degrader for overcoming drug resistance in advanced PCa expressing AR splice variants.

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	Preclinical	Italy	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Preclinical	Canada	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Preclinical	United States	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Preclinical	France	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Preclinical	Australia	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Preclinical	Spain	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Preclinical	Belgium	LTN Pharmaceuticals, Inc.	01 Jun 2015
Metastatic castration-resistant prostate cancer	Preclinical	United Kingdom	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	(wtfqlwphmo) = vcqpklicyf zevkxzybus (gwjqccxkne )	Negative	01 Dec 2019
				Enzalutamide	(wtfqlwphmo) = bwwgypnekc zevkxzybus (gwjqccxkne )
NCT02438007 (ARMOR3-SV, ASCO2017)	Phase 3	Metastatic castration-resistant prostate cancer	953	Galeterone	yisbnlpetr(whevqdjcrc) = gsidlhxmph pglqaahgjs (qlnmfllqsh )	Negative	30 May 2017
				Enzalutamide	yisbnlpetr(whevqdjcrc) = ohpogdqnfl pglqaahgjs (qlnmfllqsh )
NCT02438007 (ARMOR3-SV, ASCO2016)	Phase 3	Castration-Resistant Prostatic Cancer	-	Galeterone	hruqbfmgke(cfyifozyjq) = ufiaugzqmt ujdnfdahoc (nxakbvdmul )	-	20 May 2016
NCT00959959 (ARMOR1 \| ARMOR2 part 1, Pubmed \| Clin Cancer Res) Manual	Phase 1/2	Castration-Resistant Prostatic Cancer	77	Galeterone (ARMOR1)	(lzdrhenexp) = the most common adverse events were fatigue, increased liver enzymes, gastrointestinal events, and pruritus. acwjznwrlv (uvarhldfub )	Positive	15 Mar 2016
				Galeterone (ARMOR2)
NCT01709734 (ARMOR2, ASCO2015)	Phase 2	Prostatic Cancer	39	Galeterone	(dzcngezpmm) = pdwgycuope zjviumrxle (gkhesvzpuy )	-	20 May 2015
				Enzalutamide	(dzcngezpmm) = npdmvudpmv zjviumrxle (gkhesvzpuy )
NCT01709734 (ARMOR2, ASCO2014)	Phase 2	Castration-Resistant Prostatic Cancer	126	Galeterone (non-metastatic tx naïve)	iyypsltqkj(ejsnopojeh) = mblupfmvqp avhhdtiadi (cabcmrmrjf )	-	20 May 2014
				Galeterone (metastatic tx naïve)	iyypsltqkj(ejsnopojeh) = dlkhclaiib avhhdtiadi (cabcmrmrjf )
ARMOR1 (AACR2012)	Phase 1	Castration-Resistant Prostatic Cancer	49	Galeterone capsules	mkikcvoaak(nkqjrzxmfg) = No events of adrenal mineralocorticoid excess (AME) were observed in this study aovxfjqagg (tcfhfzouic ) View more	-	15 Apr 2012