Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras

Takwale, Akshay D.; Jo, Seunghyun; Jeon, Yeong Uk; Kim, Hyung Soo; Shin, Choong Hoon; Lee, Heung Kyoung; Ahn, Sunjoo; Lee, Chong Ock; Ha, Jae Du; Kim, Jeong-Hoon; Hwang, Jong Yeon

doi:10.1016/j.ejmech.2020.112769

Cited by 52 publications

(31 citation statements)

References 29 publications

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“…Except for these targets, the following proteins related to cancer cell proliferation could also be targeted by PROATCs: AR [ 7 , 106 , 108 – 111 , 155 , 156 ], ALK [ 22 , 52 , 113 , 116 , 157 ], BLK [ 118 ], BRD7/9 [ 82 , 83 , 120 , 158 ], CDK2/5 [ 84 ], CDK8 [ 112 ], CDK9 [ 38 , 114 , 115 , 117 , 159 ], Cdc20 [ 119 ], c-Met [ 79 ], CREPT [ 121 ], CYP1B1 [ 122 ], DHODH [ 123 ], ER [ 89 , 124 , 126 , 128 , 160 ], ERK1/2 [ 26 ], FLT-3 [ 132 , 161 ], HER2 [ 79 ], MEK1/2 [ 85 , 86 , 162 ], KRAS G12C [ 87 , 163 ], GSPT1 [ 125 ], PLK1 [ 127 ], SLC9A1 [ 129 ], TACC3 [ 130 ], TRIM24 [ 131 ], TRKA/C [ 133 , 164 ], Wee1 [ 88 ], α 1A -AR [ 134 ].…”

Section: Protacs In Targeted Cancer Therapymentioning

confidence: 99%

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Zheng

et al. 2022

Mol Cancer

127

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Proteolysis-targeting chimeras (PROTACs) are engineered techniques for targeted protein degradation. A bifunctional PROTAC molecule with two covalently-linked ligands recruits target protein and E3 ubiquitin ligase together to trigger proteasomal degradation of target protein by the ubiquitin-proteasome system. PROTAC has emerged as a promising approach for targeted therapy in various diseases, particularly in cancers. In this review, we introduce the principle and development of PROTAC technology, as well as the advantages of PROTACs over traditional anti-cancer therapies. Moreover, we summarize the application of PROTACs in targeting critical oncoproteins, provide the guidelines for the molecular design of PROTACs and discuss the challenges in the targeted degradation by PROTACs.

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Section: Protacs In Targeted Cancer Therapymentioning

confidence: 99%

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Zheng

et al. 2022

Mol Cancer

127

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“…Other AR-targeted PROTAC molecules with animal testing data include TD-802 (DC 50 = 12.5 nM) ( 32 ) and A031 (IC 50 < 0.25 μM) ( 33 ) that promote degradation of the full-length AR protein. MTX-23 was shown to promote protein degradation of both the full-length and AR-V7 variant AR protein (DC 50 = 0.37-2 μM) ( 34 ).…”

Section: Ar Protein Elimination Approaches In Preclinical Development...mentioning

confidence: 99%

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Huang

Lin

2022

Front. Oncol.

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Prostate cancer is a major health issue in western countries and is the second leading cause of cancer death in American men. Prostate cancer depends on the androgen receptor (AR), a transcriptional factor critical for prostate cancer growth and progression. Castration by surgery or medical treatment reduces androgen levels, resulting in prostatic atrophy and prostate cancer regression. Thus, metastatic prostate cancers are initially managed with androgen deprivation therapy. Unfortunately, prostate cancers rapidly relapse after castration therapy and progress to a disease stage called castration-resistant prostate cancer (CRPC). Currently, clinical treatment for CRPCs is focused on suppressing AR activity with antagonists like Enzalutamide or by reducing androgen production with Abiraterone. In clinical practice, these treatments fail to yield a curative benefit in CRPC patients in part due to AR gene mutations or splicing variations, resulting in AR reactivation. It is conceivable that eliminating the AR protein in prostate cancer cells is a promising solution to provide a potential curative outcome. Multiple strategies have emerged, and several potent agents that reduce AR protein levels were reported to eliminate xenograft tumor growth in preclinical models via distinct mechanisms, including proteasome-mediated degradation, heat-shock protein inhibition, AR splicing suppression, blockage of AR nuclear localization, AR N-terminal suppression. A few small chemical compounds are undergoing clinical trials combined with existing AR antagonists. AR protein elimination by enhanced protein or mRNA degradation is a realistic solution for avoiding AR reactivation during androgen deprivation therapy in prostate cancers.

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“…disclosed some new AR PROTACs for the treatment of metastatic castration-resistant prostate cancer (CRPC). 41 Primarily, they utilised TD-106 (a novel CRBN ligand) as an E3 ligase ligand. Among the new CRBN-based PROTACs, PROTAC 2 ( Table 2 ) effectively degraded AR protein with a degradation concentration 50% of 12.5 nM and maximum degradation of 93% in LNCaP prostate cancer cells.…”

Section: Protacs For Cancersmentioning

confidence: 99%

Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

Wang

Zhang

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Proteolysis-targeting chimaeras (PROTACs) have been developed to be an emerging technology for targeted protein degradation and attracted the favour of academic institutions, large pharmaceutical enterprises, and biotechnology companies. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The heterobifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. To date, PROTACs targeting ∼70 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for diseases therapy. In this review, the recent advances in PROTACs against clinically validated drug targets are summarised and the chemical structure, cellular and in vivo activity, pharmacokinetics, and pharmacodynamics of these PROTACs are highlighted. In addition, the potential advantages, challenges, and prospects of PROTACs technology in disease treatment are discussed.

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Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras

Cited by 52 publications

References 29 publications

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Proteolysis-targeting chimeras (PROTACs) in cancer therapy

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

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