DT-061

DT-061 is an activator of a heterotrimeric protein phosphatase 2A (PP2A) complex containing the PP2A-B56α regulatory B subunit.^1,2,3,4 It increases the affinity of PP2A-B56α to a PP2A-A and PP2A-C dimer, however, it does not induce phosphate release in a cell-free assay using B55α, B56α, or B56ε as the regulatory subunits.^2,3 DT-061 decreases ceramide (Cer) and hexosylceramide molar ratios and increases sphingomyelin (SM) molar ratios in relation to phosphatidylcholine (PC) in MCF-7 cells cultured with sphingosine and disrupts Golgi and endoplasmic reticulum integrity in HeLa cells.³ In vivo, DT-061 (5 mg/kg) reduces tumor volume in an NCI H358 non-small cell lung cancer (NSCLC) mouse xenograft using cells that express wild-type PP2A-A but not those that express an arginine-to-tryptophan mutation at position 183 (PP2A-A^R183W), a mutation that disrupts the ability of PP2A-A to bind to PP2A-B56α.² It also increases allograft survival in a murine heart transplantation model when administered at a dose of 5 mg/kg.⁵

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1. Sangodkar, J., Perl, A., Tohme, R., et al. Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth. J. Clin. Invest. 27(6), 2081-2090 (2017).

2. Leonard, D., Huang, W., Izadmehr, S., et al. Selective PP2A enhancement through biased heterotrimer stabilization. Cell, 181(183) (2020).

3. 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).

4. Leonard, D., Huang, W., Brautigan, D.L., et al. A reply to “Cellular toxicity of iHAP1 and DT-061 does not occur through PP2A-B56 targeting". (2021).

5. Zhou, X., Xu, Q., Li, W., et al. Protein phosphatase 2A activation promotes heart transplant acceptance in mice. 108(3), e36-e48 (2024).