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.
Kastrinsky, David B.,Sangodkar, Jaya,Zaware, Nilesh,Izadmehr, Sudeh,Dhawan, Neil S.,Narla, Goutham,Ohlmeyer, Michael
p. 6528 - 6534
(2015/10/05)
TRICYCLIC COMPOUNDS AS ANTICANCER AGENTS
Tricyclic chemical modulators of FOXO transcription factor proteins are disclosed. The compounds are useful to treat cancer, age-onset proteotoxicity, stress-induced depression, inflammation, and acne. The compounds are of phenothiazine, dibenzoazepine and annulene and similar genera.
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Paragraph 0094
(2013/03/26)
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