Where achievable, restoration of PP2A function inhibits cancer progression, and notably, by a mediator that is downstream of the oncogenic kinases that initiate and drive cancer progression. While several therapeutics have been developed to indirectly target PP2A, studies have uncovered small molecules such as phenothiazines that directly activate PP2A. Nevertheless, because their pronounced extrapyramidal and anti-cholinergic effects were severely dose limiting, further pursuit of phenothiazines and related dibenzazepines for treatment of cancer seems unlikely. To explore the full potential of antipsychotics as anticancer agents, we reengineered the tricyclic neuroleptics to decouple the CNS pharmacology from the anti-proliferative properties of this drug class. Iterative rounds of synthesis and optimization lead to the development of a class of small molecule activators of PP2A (SMAPs).

SMAP treatment of KRAS-mutant lung cancer cell lines induced apoptosis and decreased the phosphorylation of PP2A targets such a pERK. Xenograft and transgenic mouse models of KRAS-mutant lung cancer further demonstrated the therapeutic potential of SMAP therapy through SMAP dependent inhibition of tumor growth. Molecular analysis of these tumors showed induction of apoptosis and dephosphorylation of targets of PP2A. Biochemical studies showed that SMAPs bound to the PP2A-A subunit and induced a conformational change in PP2A. PP2A was further confirmed as the primary target of these small molecules as mutation of putative binding sites and PP2A dysregulation by SV40 small T expression inhibited the anti-tumorigenic potential of SMAP therapy in cellular and xenograft models. This work was published and featured in the Journal of Clinical Investigation.