Reengineered tricyclic anti-cancer agents.
Basic Information
ID: ALA3611968
Journal: Bioorg Med Chem
Title: Reengineered tricyclic anti-cancer agents.
Authors: Kastrinsky DB, Sangodkar J, Zaware N, Izadmehr S, Dhawan NS, Narla G, Ohlmeyer M.
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.
CiteXplore: 26372073
DOI: 10.1016/j.bmc.2015.07.007
Patent ID: ┄