1242137-15-0Relevant articles and documents
Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors
Jadhavar, Pradeep S.,Ramachandran, Sreekanth A.,Riquelme, Eduardo,Gupta, Ashu,Quinn, Kevin P.,Shivakumar, Devleena,Ray, Soumya,Zende, Dnyaneshwar,Nayak, Anjan K.,Miglani, Sandeep K.,Sathe, Balaji D.,Raja, Mohd.,Farias, Olivia,Alfaro, Ivan,Belmar, Sebastián,Guerrero, Javier,Bernales, Sebastián,Chakravarty, Sarvajit,Hung, David T.,Lindquist, Jeffrey N.,Rai, Roopa
, p. 5222 - 5228 (2016)
While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20–40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR–HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC50= 0.0356 μM and AR binding IC50= 0.03 μM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics.
Hybrid enzalutamide derivatives with histone deacetylase inhibitor activity decrease heat shock protein 90 and androgen receptor levels and inhibit viability in enzalutamide-resistant C4-2 prostate cancer cells
Rosati, Rayna,Chen, Bailing,Patki, Mugdha,Mcfall, Thomas,Ou, Siyu,Heath, Elisabeth,Ratnam, Manohar,Qin, Zhihui
, p. 225 - 237 (2016)
Histone deacetylase inhibitors (HDACIs) can disrupt the viability of prostate cancer (PCA) cells through modulation of the cytosolic androgen receptor (AR) chaperone protein heat shock protein 90 (HSP90). However, toxicities associated with their pleiotropic effects could contribute to the ineffectiveness of HDACIs in PCA treatment. We designed hybrid molecules containing partial chemical scaffolds of enzalutamide and suberoylanilide hydroxamic acid (SAHA), with weakened intrinsic pan-HDACI activities, to target HSP90 and AR in enzalutamideresistant PCA cells. The potency of the new molecules, compounds 2-75 [4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5- dimethyl-4-oxo-2- Thioxoimidazolidin-1-yl)-2-fluoro-N-(7-(hydroxyamino)- 7-oxoheptyl)benzamide] and 1005 [(E)-3-(4-(3-(4- cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2- Thioxoimidazolidin- 1-yl)-2-fluorophenyl)-N-hydroxyacrylamide], as inhibitors of nuclear and cytosolic histone deacetylases was substantially lower than that of SAHA in cell-free and in situ assays. Compounds 2-75 and 1005 antagonized gene activation by androgen without inducing chromatin association of AR. Enzalutamide had no effect on the levels of AR or HSP90, whereas the hybrid compounds induced degradation of both AR and HSP90, similar to (compound 1005) or more potently than (compound 2-75) SAHA. Similar to SAHA, compounds 2-75 and 1005 decreased the level of HSP90 and induced acetylation in a predicted approximately 55 kDa HSP90 fragment. Compared with SAHA, compound 2-75 induced greater hyperacetylation of the HDAC6 substrate a- Tubulin. In contrast with SAHA, neither hybrid molecule caused substantial hyperacetylation of histones H3 and H4. Compounds 2-75 and 1005 induced p21 and caused loss of viability in the enzalutamide-resistant C4-2 cells, with efficacies that were comparable to or better than SAHA. The results suggest the potential of the new compounds as prototype antitumor drugs that would downregulateHSP90 andAR in enzalutamide-resistant PCA cells with weakened effects on nuclear HDACI targets.
An improved and practical route for the synthesis of enzalutamide and potential impurities study
Zhou, Ai-Nan,Li, Bonan,Ruan, Lejun,Wang, Yeting,Duan, Gengli,Li, Jianqi
, p. 426 - 430 (2017)
An improved and practical synthesis of enzalutamide was accomplished in five steps. Starting from 4-bromo-2-fluoro-benzonic acid, a methyl esterification, Ullmann ligation, methyl esterification, ring closing reaction and final methyl amidation provided the target in 35% total yield with 99.8% purity. Five identified impurities were also synthesized. This efficient and economical procedure avoids the use of highly toxic reagents and multiple recrystallization operations, which is suitable for further industrialization.
Dual-function antiandrogen/HDACi hybrids based on enzalutamide and entinostat
Barrett, Ryan R.G.,Nash, Claire,Diennet, Marine,Cotnoir-White, David,Doyle, Christopher,Mader, Sylvie,Thomson, Axel A.,Gleason, James L.
supporting information, (2021/12/01)
The combination of androgen receptor antagonists with histone deacetylase inhibitors (HDACi) has been shown to be more effective than antiandrogens alone in halting growth of prostate cancer cell lines. Here we have designed, synthesized and assessed a se
Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models
Bachmaier, Rafael D.,Baltes, Fabian,Bendas, Gerd,Gütschow, Michael,Gockel, Lukas M.,Pfeifer, Vladlena,Sosi?, Izidor,Steinebach, Christian,Wagner, Karl G.
, (2022/02/16)
Although the androgen receptor (AR) is a validated target for the treatment of prostate cancer, resistance to antiandrogens necessitates the development of new therapeutic modalities. Exploiting the ubiquitin-proteasome system with proteolysis-targeting chimeras (PROTACs) has become a practical approach to degrade specific proteins and thus to extend the portfolio of small molecules used for the treatment of a broader spectrum of diseases. Herein, we present three subgroups of enzalutamide-based PROTACs in which only the exit vector was modified. By recruiting cereblon, we were able to demonstrate the potent degradation of AR in lung cancer cells. Furthermore, the initial evaluation enabled the design of an optimized PROTAC with a rigid linker that degraded AR with a DC50 value in the nanomolar range. These results provide novel AR-directed PROTACs and a clear rationale for further investigating AR involvement in lung cancer models.
METHOD FOR PREPARING DEUTERATED IMIDAZOLE DIKETONE COMPOUND
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Paragraph 0040-0044, (2020/03/28)
A method for preparation of deuterated imidazole diketone compounds includes the following steps: (1) using compound of formula (I) and compounds of formula (II) as starting material, compounds of formula (III) can be obtained by a substitution reaction; (2) Compounds of formula (IV) can be prepared by esterification of carboxyl in compounds of formula (III); (3) Cyclization of compounds of formula (IV) and compound of formula (V) provides compounds of formula (VI); (4) Compounds of formula (VI) are deesterificated and react to produce compounds of formula (VII); (5) using compounds of formula (VII) and compounds of formula (VIII) as starting material, the deuterated imidazole diketone compounds of formula (IX) are obtained by the condensation reaction of amide.
ANDROGEN RECEPTOR PROTEIN DEGRADERS
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Paragraph 0173; 0183, (2020/07/21)
The present disclosure provides compounds represented by Formula (I): A—L—B (I), and the salts or solvates thereof, wherein A, L, and B are as defined in the specification. Compounds having Formula (I) are androgen receptor degraders useful for the treatment of cancer.
Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer
Han, Xin,Wang, Chao,Qin, Chong,Xiang, Weiguo,Fernandez-Salas, Ester,Yang, Chao-Yie,Wang, Mi,Zhao, Lijie,Xu, Tianfeng,Chinnaswamy, Krishnapriya,Delproposto, James,Stuckey, Jeanne,Wang, Shaomeng
, p. 941 - 964 (2019/01/21)
We report herein the discovery of highly potent PROTAC degraders of androgen receptor (AR), as exemplified by compound 34 (ARD-69). ARD-69 induces degradation of AR protein in AR-positive prostate cancer cell lines in a dose- and time-dependent manner. ARD-69 achieves DC50 values of 0.86, 0.76, and 10.4 nM in LNCaP, VCaP, and 22Rv1 AR+ prostate cancer cell lines, respectively. ARD-69 is capable of reducing the AR protein level by >95% in these prostate cancer cell lines and effectively suppressing AR-regulated gene expression. ARD-69 potently inhibits cell growth in these AR-positive prostate cancer cell lines and is >100 times more potent than AR antagonists. A single dose of ARD-69 effectively reduces the level of AR protein in xenograft tumor tissue in mice. Further optimization of ARD-69 may ultimately lead to a new therapy for AR+, castration-resistant prostate cancer.
Compound and composition as well as application thereof to drugs preparation
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Paragraph 0062; 0074-0076, (2019/01/08)
The present invention relates to a compound having a structure of formula I or a pharmaceutically acceptable salt of the compound. Regarding the compound, R1 is selected from hydrogen, fluorine, and chlorine; R2 and R3 are independently selected from hydr
ANTICANCER DRUGS INCLUDING THE CHEMICAL STRUCTURES OF AN ANDROGEN RECEPTOR LIGAND AND A HISTONE DEACETYLASE INHIBITOR
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Paragraph 0114, (2017/08/26)
A novel class of drugs for treating androgen receptor (AR) positive cancer including prostate cancer and breast cancer are described. The drugs include the chemical scaffolds of a high affinity androgen receptor ligand and a histone deacetylase inhibitor. Also described are compositions including the novel drugs and methods of treating AR positive cancer using the compositions.
