162046-66-4Relevant articles and documents
Protein degradation targeting chimera for degrading androgen receptor
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, (2021/07/24)
The invention relates to a novel difunctional molecule compound based on VHL ligand induction and application of the difunctional molecule compound in synthesis of the compounds and pharmaceutical compositions thereof. The compound is shown as a formula I. The compound can selectively induce AR protein degradation and can be used for treating cancers such as prostatic cancer and breast cancer.
Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras
Takwale, Akshay D.,Jo, Seung-Hyun,Jeon, Yeong Uk,Kim, Hyung Soo,Shin, Choong Hoon,Lee, Heung Kyoung,Ahn, Sunjoo,Lee, Chong Ock,Du Ha, Jae,Kim, Jeong-Hoon,Hwang, Jong Yeon
, (2020/09/23)
Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of androgen receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study.
Benzamide capped peptidomimetics as non-ATP competitive inhibitors of CDK2 using the REPLACE strategy
Premnath, Padmavathy Nandha,Craig, Sandra N.,Liu, Shu,McInnes, Campbell
supporting information, p. 3754 - 3760 (2016/07/22)
Inhibition of cyclin dependent kinase 2 (CDK2) in complex with cyclin A in G1/S phase of the cell cycle has been shown to promote selective apoptosis of cancer cells through the E2F1 pathway. An alternative approach to catalytic inhibition is to target the substrate recruitment site also known as the cyclin binding groove (CBG) to generate selective non-ATP competitive inhibitors. The REPLACE strategy has been applied to identify fragment alternatives and substituted benzoic acid derivatives were evaluated as a promising scaffold to present appropriate functionality to mimic key peptide determinants. Fragment Ligated Inhibitory Peptides (FLIPs) are described which potently inhibit both CDK2/cyclin A and CDK4/cyclin D1 and have preliminary anti-tumor activity. A structural rationale for binding was obtained through molecular modeling further demonstrating their potential for further development as next generation non ATP competitive CDK inhibitors.