iHAP1

iHAP1 is an inhibitor of tubulin polymerization (IC₅₀ = 0.87 µM in a cell-free assay) that was originally identified as an activator of a heterotrimeric protein phosphatase 2A (PP2A) complex containing the PP2A-B56ε regulatory B subunit in a study that has since been retracted.^1,2,3 It does not bind to protein phosphatase 2 regulatory subunit 1A (PPP2R1A) when used at a concentration of 20 µM nor activate PP2A-B55α, PP2A-B56α, or PP2A-B56ε in a cell-free dephosphorylation assay at 10 µM.⁴ iHAP1 inhibits the proliferation of K562 leukemia cells (IC₅₀ = 0.84 µM) and induces apoptosis in HeLa cells when used at a concentration of 0.5 µM.^1,4 iHAP1 also inhibits acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC₅₀ values of 5.9 and 5.3 µM, respectively.⁵

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1. Prinz, H., Chamasmani, B., Vogel, K., et al. N-benzoylated phenoxazines and phenothiazines: Synthesis, antiproliferative activity, and inhibition of tubulin polymerization. J. Med. Chem. 54(12), 4247-4263 (2011).

2. Morita, K., He, S., Nowak, R.P., et al. Allosteric activators of protein phosphatase 2A display broad antitumor activity mediated by dephosphorylation of MYBL2. Cell 181(3), 702-715.e720 (2020).

3. Morita, K., He, S., Nowak, R.P., et al. Retraction Notice to: Allosteric activators of protein phosphatase 2A display broad antitumor activity mediated by dephosphorylation of MYBL2. Cell 185(16), 3058 (2022).

4. Vit, G., Duro, J., Rajendraprasad, G., et al. Chemogenetic profiling reveals PP2A-independent cytotoxicity of proposed PP2A activators iHAP1 and DT-061. EMBO J. 41(14), e110611 (2022).

5. Tin, G., Mohamed, T., Gondora, N., et al. Tricyclic phenothiazine and phenoselenazine derivatives as potential multi-targeting agents to treat Alzheimer’s disease. Med. Chem. Comm. 6, 1930-1941 (2015).