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.
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.
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.
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.
