1423077-10-4Relevant articles and documents
Reengineered tricyclic anti-cancer agents
Kastrinsky, David B.,Sangodkar, Jaya,Zaware, Nilesh,Izadmehr, Sudeh,Dhawan, Neil S.,Narla, Goutham,Ohlmeyer, Michael
, p. 6528 - 6534 (2015/10/05)
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.