1417653-47-4Relevant academic research and scientific papers
A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators
Ferrara, Skylar J.,Scanlan, Thomas S.
, p. 9742 - 9751 (2020/10/19)
The blood-brain barrier is a major impediment for targeted central nervous system (CNS) therapeutics, especially with carboxylic acid-containing drugs. Nuclear receptor modulators, which often feature carboxylic acid motifs for target engagement, have emerged as a class of potentially powerful therapeutics for neurodegenerative CNS diseases. Herein is described a prodrug strategy that directs the biodistribution of parent drug nuclear receptor modulators into the CNS while masking them as functional receptor ligands in the periphery. This prodrug strategy targets a specific amidase, fatty acid amide hydrolase (FAAH), an enzyme with enriched expression in the CNS. Our results demonstrate that this prodrug strategy can be generalized to a variety of carboxylic acid-containing drug structures that satisfy the structural requirements of blood-brain barrier diffusion and FAAH substrate recognition.
AMIDE PRODRUGS OF SMALL MOLECULE NUCLEAR RECEPTOR MODULATORS
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Page/Page column 12; 16, (2019/09/18)
Provided herein are novel amide prodrug forms of pharmaceutically active agents useful for central nervous system disorders.
Small molecule inhibitors of PCNA/PIP-box interaction suppress translesion DNA synthesis
Actis, Marcelo,Inoue, Akira,Evison, Benjamin,Perry, Scott,Punchihewa, Chandanamali,Fujii, Naoaki
supporting information, p. 1972 - 1977 (2013/04/24)
Proliferating cell nuclear antigen (PCNA) is an essential component for DNA replication and DNA damage response. Numerous proteins interact with PCNA through their short sequence called the PIP-box to be promoted to their respective functions. PCNA supports translesion DNA synthesis (TLS) by interacting with TLS polymerases through PIP-box interaction. Previously, we found a novel small molecule inhibitor of the PCNA/PIP-box interaction, T2AA, which inhibits DNA replication in cells. In this study, we created T2AA analogues and characterized them extensively for TLS inhibition. Compounds that inhibited biochemical PCNA/PIP-box interaction at an IC50 a reporter plasmid that was globally damaged by cisplatin, suggesting that the inhibitors blocked the TLS that allows replication of the plasmid. PCNA inhibitors increased γH2AX induction and cell viability reduction mediated by cisplatin. Taken together, these findings suggest that inhibitors of PCNA/PIP-box interaction could chemosensitize cells to cisplatin by inhibiting TLS.
SUBSTITUTED 4-PHENOXYPHENOL ANALOGS AS MODULATORS OF PROLIFERATING CELL NUCLEAR ANTIGEN ACTIVITY
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Paragraph 00475; 00487, (2013/03/26)
In one aspect, the invention relates to substituted 4-phenoxyphenol analogs, derivatives thereof, and related compounds,which are useful as inhibitors of proliferating cell nuclear antigen (PCNA); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating hyperproliferative disorders associated with PCNA using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention
