title: Reengineered tricyclic anti-cancer agents.
abstract: The phenothiazine and dibenzazepine tricyclics are potent neurotropic drugs with a documented but underutilized anti-cancer side effect. Reengineering these agents (TFP, CPZ, CIP) by replacing the basic amine with a neutral polar functional group (e.g., RTC-1, RTC-2) abrogated their CNS effects as demonstrated by in vitro pharmacological assays and in vivo behavioral models. Further optimization generated several phenothiazines and dibenzazepines with improved anti-cancer potency, exemplified by RTC-5. This new lead demonstrated efficacy against a xenograft model of an EGFR driven cancer without the neurotropic effects exhibited by the parent molecules. Its effects were attributed to concomitant negative regulation of PI3K-AKT and RAS-ERK signaling.
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
authors.forename: David B
authors.initials: DB
authors.lastname: Kastrinsky
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
authors.forename: Jaya
authors.initials: J
authors.lastname: Sangodkar
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
authors.forename: Nilesh
authors.initials: N
authors.lastname: Zaware
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
authors.forename: Sudeh
authors.initials: S
authors.lastname: Izadmehr
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
authors.forename: Neil S
authors.initials: NS
authors.lastname: Dhawan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States; Department of Medicine, Institute for Transformative Molecular Medicine, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, United States.
authors.forename: Goutham
authors.initials: G
authors.lastname: Narla
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States. Electronic address: michael.ohlmeyer@mssm.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Ohlmeyer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003984:Dibenzazepines / Q000737:chemistry; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010640:Phenothiazines / Q000737:chemistry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003984:Dibenzazepines; D006575:Heterocyclic Compounds, 3-Ring; D010640:Phenothiazines; D050493:Vesicular Monoamine Transport Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C031637:phenothiazine; C527817:dibenzazepine
keywords: Clomipramine; Dibenzazepine; Neuroleptic; Phenothiazine; Tricyclic