title: 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.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Saheem A
authors.initials: SA
authors.lastname: Zaidi
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Arnatt
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA. Electronic address: xywang@vcu.edu.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA 23298, USA. Electronic address: yzhang2@vcu.edu.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D011070:Poly I-C / Q000037:antagonists & inhibitors; D051117:Scavenger Receptors, Class A / Q000037:antagonists & inhibitors*; D012676:Senna Extract / Q000737:chemistry / Q000494:pharmacology; D000081226:Sennosides; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects; D051193:Toll-Like Receptors / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects; D001616:beta-Galactosidase / Q000037:antagonists & inhibitors
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D051117:Scavenger Receptors, Class A; D000081226:Sennosides; D054852:Small Molecule Libraries; D051193:Toll-Like Receptors; D014157:Transcription Factors; D012676:Senna Extract; D001616:beta-Galactosidase; D011070:Poly I-C; C020491:rhein
keywords: Cancer therapy; Cysteine-rich domain; Homology model; Natural product; Rhein; Scavenger receptor A