title: Novel C-4 heteroaryl 13-cis-retinamide Mnk/AR degrading agents inhibit cell proliferation and migration and induce apoptosis in human breast and prostate cancer cells and suppress growth of MDA-MB-231 human breast and CWR22Rv1 human prostate tumor xenografts in mice.
abstract: The synthesis and in vitro and in vivo antibreast and antiprostate cancers activities of novel C-4 heteroaryl 13-cis-retinamides that modulate Mnk-eIF4E and AR signaling are discussed. Modifications of the C-4 heteroaryl substituents reveal that the 1H-imidazole is essential for high anticancer activity. The most potent compounds against a variety of human breast and prostate cancer (BC/PC) cell lines were compounds 16 (VNHM-1-66), 20 (VNHM-1-81), and 22 (VNHM-1-73). In these cell lines, the compounds induce Mnk1/2 degradation to substantially suppress eIF4E phosphorylation. In PC cells, the compounds induce degradation of both full-length androgen receptor (fAR) and splice variant AR (AR-V7) to inhibit AR transcriptional activity. More importantly, VNHM-1-81 has strong in vivo antibreast and antiprostate cancer activities, while VNHM-1-73 exhibited strong in vivo antibreast cancer activity, with no apparent host toxicity. Clearly, these lead compounds are strong candidates for development for the treatments of human breast and prostate cancers.
authors: Department of Pharmacology, ‡Center for Biomolecular Therapeutics, and §Marlene Stewart Greenebaum Cancer Center, University of Maryland School of Medicine , 685 West Baltimore Street, Baltimore, Maryland 21201-1559, United States.
authors: Hannah W
authors: HW
authors: Mbatia
authors: Senthilmurugan
authors: S
authors: Ramalingam
authors: Vidya P
authors: VP
authors: Ramamurthy
authors: Marlena S
authors: MS
authors: Martin
authors: Andrew K
authors: AK
authors: Kwegyir-Afful
authors: Vincent C O
authors: VC
authors: Njar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D039561:Eukaryotic Initiation Factor-4E / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011941:Receptors, Adrenergic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D011941:Receptors, Adrenergic; D014212:Tretinoin; D017346:Protein Serine-Threonine Kinases
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