title: Novel Imidazopyridine Derivatives Possess Anti-Tumor Effect on Human Castration-Resistant Prostate Cancer Cells.
abstract: Prostate cancer (PCa) is the second leading cause of cancer-related death afflicting United States males. Most treatments to-date for metastatic PCa include androgen-deprivation therapy and second-generation anti-androgens such as abiraterone acetate and enzalutamide. However, a majority of patients eventually develop resistance to these therapies and relapse into the lethal, castration-resistant form of PCa to which no adequate treatment option remains. Hence, there is an immediate need to develop effective therapeutic agents toward this patient population. Imidazopyridines have recently been shown to possess Akt kinase inhibitory activity; thus in this study, we investigated the inhibitory effect of novel imidazopyridine derivatives HIMP, M-MeI, OMP, and EtOP on different human castration-resistant PCa cells. Among these compounds, HIMP and M-MeI were found to possess selective dose- and time-dependent growth inhibition: they reduced castration-resistant PCa cell proliferation and spared benign prostate epithelial cells. Using LNCaP C-81 cells as the model system, these compounds also reduced colony formation as well as cell adhesion and migration, and M-MeI was the most potent in all studies. Further investigation revealed that while HIMP primarily inhibits PCa cell growth via suppression of PI3K/Akt signaling pathway, M-MeI can inhibit both PI3K/Akt and androgen receptor pathways and arrest cell growth in the G2 phase. Thus, our results indicate the novel compound M-MeI to be a promising candidate for castration-resistant PCa therapy, and future studies investigating the mechanism of imidazopyridine inhibition may aid to the development of effective anti-PCa agents.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Ingersoll
authors.affiliation: Department of Chemistry, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Anastesia S
authors.initials: AS
authors.lastname: Lyons
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Sakthivel
authors.initials: S
authors.lastname: Muniyan
authors.affiliation: Department of Chemistry, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Napoleon
authors.initials: N
authors.lastname: D'Cunha
authors.affiliation: Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Tashika
authors.initials: T
authors.lastname: Robinson
authors.affiliation: College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Kyle
authors.initials: K
authors.lastname: Hoelting
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; Section of Urology, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Jennifer G
authors.initials: JG
authors.lastname: Dwyer
authors.affiliation: Department of Chemistry, Clark Atlanta University, Atlanta, Georgia, United States of America; Laboratory for Electro-Optical Materials & NASA Center for High Performance Polymers and Composites, Clark Atlanta University, Atlanta, Georgia, United States of America.
authors.forename: Xiu R
authors.initials: XR
authors.lastname: Bu
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Surinder K
authors.initials: SK
authors.lastname: Batra
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; Section of Urology, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, 807, ROC.
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011944:Receptors, Androgen / Q000378:metabolism
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D011725:Pyridines; D011944:Receptors, Androgen; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt