Small molecule inhibits activity of scavenger receptor A: Lead identification and preliminary studies.

Abstract

Scavenger receptor A (SRA) has been implicated in the processes of tumor invasion and acts as an immunosuppressor during therapeutic cancer vaccination. Pharmacological inhibition of SRA function thus holds a great potential to improve treatment outcome of cancer therapy. Macromolecular natural product sennoside B was recently shown to block SRA function. Here we report the identification and characterization of a small molecule SRA inhibitor rhein. Rhein, a deconstructed analog of sennoside B, reversed the suppressive activity of SRA in dendritic cell-primed T cell activation, indicated by transcription activation of il2 gene and production of IL-2. Rhein also inhibited SRA ligand polyinosinic:polycytidylic acid (poly(I:C)) induced activation of transcriptional factors, including interferon regulatory factor 3 (IRF3) and signal transducer and activator of transcription 1 (STAT1). Additionally, this newly identified lead compound was docked into the homology models of the SRA cysteine rich domain to gain insights into its interaction with the receptor. It was then found that rhein can favorably interact with SRA cysteine rich domain. Collectively, rhein, being the first identified small molecule inhibitors for SRA, warrants further structure-activity relationship studies, which may lead to development of novel pharmacological intervention for cancer therapy.

• Authors: Yunyun Yuan, Xia Li, Saheem A Zaidi, Christopher K Arnatt, Xiaofei Yu, Chunqing Guo, Xiang-Yang Wang, Yan Zhang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 16 Pg. 3179-83 (Aug 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26094120 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Ltd.

Chemical References

• Anthraquinones
• Antineoplastic Agents
• IRF3 protein, human
• Interferon Regulatory Factor-3
• Scavenger Receptors, Class A
• Sennosides
• Small Molecule Libraries
• Toll-Like Receptors
• Transcription Factors
• Senna Extract
• beta-Galactosidase
• Poly I-C
• rhein

Topics

• Animals
• Anthraquinones (chemical synthesis, pharmacology)
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Dendritic Cells (drug effects)
• Drug Design
• Humans
• Interferon Regulatory Factor-3 (antagonists & inhibitors)
• Lymphocyte Activation (drug effects)
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Molecular
• Poly I-C (antagonists & inhibitors)
• Scavenger Receptors, Class A (antagonists & inhibitors)
• Senna Extract (chemistry, pharmacology)
• Sennosides
• Small Molecule Libraries
• Structure-Activity Relationship
• T-Lymphocytes (drug effects)
• Toll-Like Receptors (drug effects)
• Transcription Factors (drug effects)
• beta-Galactosidase (antagonists & inhibitors)