Morita K, He S, Nowak RP, Wang J, Zimmerman MW, Fu C, Durbin AD, Martel MW, Prutsch N, Gray NS, Fischer ES, and Look AT
Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class of small-molecule iHAPs (improved heterocyclic activators of PP2A) that kill leukemia cells by allosterically assembling a specific heterotrimeric PP2A holoenzyme consisting of PPP2R1A (scaffold), PPP2R5E (B56ε, regulatory), and PPP2CA (catalytic) subunits. One compound, iHAP1, activates this complex but does not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase. In contrast, SMAPs, a separate class of compounds, activate PP2A holoenzymes containing a different regulatory subunit, do not dephosphorylate MYBL2, and arrest tumor cells in G1 phase. Our findings demonstrate that small molecules can serve as allosteric switches to activate distinct PP2A complexes with unique substrates., Competing Interests: Declaration of Interests E.S.F. is a member of the scientific advisory board of C4 Therapeutics and a consultant to Novartis and Deerfield. He is a science advisory board member, founder, and shareholder for Civetta Therapeutics. E.S.F. received research funding from Novartis, Deerfield, and Astellas not related to this work. N.S.G. is a founder, science advisory board member, and equity holder in Gatekeeper, Syros, Petra, C4, B2S, and Soltego. The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Janssen, Kinogen, Voronoi, Her2llc, Deerfield, and Sanofi. A patent application related to this work has been submitted to the U.S. Patent and Trademark Office entitled “Compositions and Methods of Treating Cancers by Administering a Phenothiazine-Related Drug that Activates Protein Phosphatase 2A (PP2A) with Reduced Inhibitory Activity Targeted to the Dopamine D2 Receptor and Accompanying Toxicity” (application no. PCT/US19/67508)., (Copyright © 2020 Elsevier Inc. All rights reserved.)