2. Academic Validation
  3. Reengineered tricyclic anti-cancer agents

Reengineered tricyclic anti-cancer agents

  • Bioorg Med Chem. 2015 Oct 1;23(19):6528-34. doi: 10.1016/j.bmc.2015.07.007.
David B Kastrinsky 1,  Jaya Sangodkar 2,  Nilesh Zaware 1,  Sudeh Izadmehr 2,  Neil S Dhawan 2,  Goutham Narla 3,  Michael Ohlmeyer 4
Affiliations

Affiliations

  • 1 Department of Structural and Chemical Biology, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
  • 2 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mt. Sinai, 1425 Madison Avenue, New York, NY 10029, United States.
  • 3 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.
  • 4 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.
PMID: 26372073 DOI: 10.1016/j.bmc.2015.07.007
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.

Keywords

Clomipramine; Dibenzazepine; Neuroleptic; Phenothiazine; Tricyclic.

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