145916-41-2Relevant articles and documents
Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs
Velagapudi, Sai Pradeep,Costales, Matthew G.,Vummidi, Balayeshwanth R.,Nakai, Yoshio,Angelbello, Alicia J.,Tran, Tuan,Haniff, Hafeez S.,Matsumoto, Yasumasa,Wang, Zi Fu,Chatterjee, Arnab K.,Childs-Disney, Jessica L.,Disney, Matthew D.
, p. 1086 - 7,1094 (2018)
Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors. The latter avidly bound the motif found in the Dicer site of oncogenic microRNA (miR)-21 and inhibited its processing both in vitro and in cells. The most potent compound de-repressed a downstream protein target and inhibited a miR-21-mediated invasive phenotype. The compound's activity was ablated upon overexpression of pre-miR-21. Target validation via chemical crosslinking and isolation by pull-down showed direct engagement of pre-miR-21 by the small molecule in cells, demonstrating that RNAs should indeed be considered druggable. RNA is an emerging target for small molecules, but has it been an established one all along? Velagapudi et al. profiled the binding of medicines to thousands of RNA motifs, showing that broad drug classes bind RNA. Indeed, approved anti-cancer drugs target an oncogenic non-coding RNA, affecting its phenotype.
TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
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Paragraph 0568; 0569; 1280; 1281, (2021/02/12)
The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
A "click Chemistry Platform" for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation
Wurz, Ryan P.,Dellamaggiore, Ken,Dou, Hannah,Javier, Noelle,Lo, Mei-Chu,McCarter, John D.,Mohl, Dane,Sastri, Christine,Lipford, J. Russell,Cee, Victor J.
supporting information, p. 453 - 461 (2018/02/07)
Proteolysis targeting chimeras (PROTACs) are bispecific molecules containing a target protein binder and an ubiquitin ligase binder connected by a linker. By recruiting an ubiquitin ligase to a target protein, PROTACs promote ubiquitination and proteasomal degradation of the target protein. The generation of effective PROTACs depends on the nature of the protein/ligase ligand pair, linkage site, linker length, and linker composition, all of which have been difficult to address in a systematic way. Herein, we describe a "click chemistry" approach for the synthesis of PROTACs. We demonstrate the utility of this approach with the bromodomain and extraterminal domain-4 (BRD4) ligand JQ-1 (3) and ligase binders targeting cereblon (CRBN) and Von Hippel-Lindau (VHL) proteins. An AlphaScreen proximity assay was used to determine the ability of PROTACs to form the ternary ligase-PROTAC-target protein complex and a MSD assay to measure cellular degradation of the target protein promoted by PROTACs.
