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.

Phosphoproteomics Profiling of Nonsmall Cell Lung Cancer Cells Treated with a Novel Phosphatase Activator

“…Note that one technical replicate in the treated A549 group was ultimately excluded due to poor detection of phosphoenriched peptides. Based on optimization studies (unpublished), a 12 h time‐point allowed for reproducible dephosphorylation of ERK1/2, a target previously shown to be differentially phosphorylated with SMAP, without induction of apoptosis. This strategy was intended to limit the secondary signaling that may accumulate from cell death.…”

“…More recently, the pro‐apoptotic and antitumor properties of a class of antipsychotic drugs have been described, and their anticancer activity has been attributed to their ability to activate PP2A . Reverse engineering of these drugs resulted in a first‐in‐class series of small molecule activators of PP2A (SMAPs) that activates this family of phosphatases but lacks the main dose‐limiting toxicities associated with the parent molecules . Follow‐up assays in nonsmall cell lung cancer (NSCLC) models have confirmed that these molecules bind to the PP2A trimer, and they demonstrated proapoptotic, antiproliferative properties that are blunted upon PP2A inhibition…”

Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth

“…Fingolimod FTY720 and its chiral deoxy analog drugs were used to indirectly reactivate PP2A by partly blocking the PP2A inhibitor protein SET (38). However, direct activation of the tumor-suppressor PP2A is observed with phenothiazines that directly bind the scaffold PP2A Aα subunit (16). Therefore, we generated a series of SMAPs by decoupling the CNS pharmacology from the antiproliferative properties of phenothiazines.…”

Targeting PP2A in cancer: Combination therapies

“…Certain strategies directly target PP2A by using small molecules that bind to the scaffolding subunit resulting in conformational changes which lead to activation of the holoenzyme. These small molecules include perphenazine, a tricyclic neuroleptic, and SMAP, a re-engineered tricyclic sulfonamide [24-26]. More commonly, PP2A endogenous inhibitors are targeted for inhibition (Figure 1).…”