Prostate Cancer (PCa) easily progress to metastatic Castration-Resistant Prostate Cancer (mCRPC) that remains a significant cause of cancer-related death. Androgen receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Proteolysis-targeting chimaera (PROTAC) technology based on Hydrophobic Tagging (HyT) represents an intriguing strategy to regulate the function of therapeutically androgen receptor proteins. In the present study, we have designed, synthesized, and evaluated a series of PROTAC-HyT AR degraders using AR antagonists, RU59063, which were connected with adamantane-based hydrophobic moieties by different alkyl chains. Compound D-4-6 exhibited significant AR protein degradation activity, with a degradation rate of 57 % at 5 μM and nearly 90 % at 20 μM in 24 h, and inhibited the proliferation of LNCaP cells significantly with an IC₅₀ value of 4.77 ± 0.26 μM in a time-concentration-dependent manner. In conclusion, the present study lays the foundation for the development of a completely new class of therapeutic agents for the treatment of mCRPC, and further design and synthesis of AR-targeting degraders are currently in progress for better degradation rate.

01 Nov 2004·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Synthesis and structure–activity investigation of iodinated arylhydantoins and arylthiohydantoins for development as androgen receptor radioligands

Q4 · MEDICINE

Article

Author: Yong Woon Jung ; Marcian E. Van Dort

A series of side-chain derivatives of the arylhydantoin RU 58841 and the arylthiohydantoin RU 59063, wherein the aromatic trifluoromethyl group was replaced with iodine, was synthesized for possible development as radioiodinated androgen receptor (AR) ligands. Derivatives containing the cyanomethyl, methoxyethyl and propenyl side-chains displayed moderately high affinity (K(i)=20-59nM) towards the rat AR. Side-chains containing bulky lipophilic groups such as, benzyl and phenylpropyl, were poorly tolerated (K(i)>219nM). Superior AR binding affinities (0.71nM

01 Aug 2000·Journal of Medicinal ChemistryQ1 · MEDICINE

Design, Synthesis, and Pharmacological Characterization of 4-[4,4-Dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]- 2-iodobenzonitrile as a High-Affinity Nonsteroidal Androgen Receptor Ligand

Q1 · MEDICINE

Article

Author: Wayburn, Bess ; Van Dort, Marcian E. ; Robins, Diane M.

4-[4, 4-Dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-+ ++trif luoromethylbenzonitrile (RU 59063) is a prototype of a new class of high-affinity nonsteroidal androgen receptor (AR) ligands. The search for a radioiodinated AR ligand prompted us to synthesize 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-i odo benzonitrile (DTIB) wherein the trifluoromethyl group of RU 59063 was substituted with the similarly hydrophobic iodine atom. DTIB displayed subnanomolar binding affinity (K(i) = 0.71 +/- 0.22 nM) for the rat AR in competitive binding assays. Additionally, DTIB demonstrated potent agonist activity, comparable to that of the natural androgen 5alpha-dihydrotestosterone (DHT), in a cell-based functional assay (cotransfection assay). DTIB represents a new lead for the development of high-affinity radioiodinated AR radioligands.

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Indication	Highest Phase	Country/Location	Organization	Date
Acne Vulgaris	Discovery	FR	Hoechst Marion Roussel SA	-
Hirsutism	Discovery	FR	Hoechst Marion Roussel SA	-

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