PP242

The mammalian target of rapamycin (mTOR) is a serine-threonine kinase that is central to two protein complexes, mTORC1 and mTORC2. These complexes are differentially regulated (e.g., only mTORC1 is sensitive to rapamycin) and regulate different pathways. PP242 is an inhibitor of the active site of mTOR kinase in both mTORC1 and mTORC2 (IC₅₀ = 8 nM).^1,2 It less effectively inhibits PKCα, PI3-kinase subunit p110γ, JAK2, PKCβI, and PKCβII (IC₅₀ = 49, 102, 110, 198, and 185, respectively).^2,3 PP242 has been shown to cause the death of certain human and murine leukemia cells more potently than rapamycin and, in vivo, delays leukemia onset and augments the effects of tyrosine kinase inhibitors in suppressing leukemic expansion and extending survival.⁴

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1. Apsel, B., Blair, J.A., Gonzalez, B., et al. Targeted polypharmacology: Discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat. Chem. Biol. 4(11), 691-699 (2008).

2. Feldman, M.E., Apsel, B., Uotila, A., et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7(2), 0371-0383 (2009).

3. Kojima, F., Kapoor, M., Kawai, S., et al. Prostaglandin E₂ activates Rap1 via EP₂/EP₄ receptors and cAMP-signaling in rheumatoid synovial fibroblasts: Involvement of Epac1 and PKA. Prostaglandins Other Lipid Mediat. 89(1-2), 26-33 (2009).

4. Janes, M.R., Limon, J.J., So, L., et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat. Med. 16(2), 205-213 (2010).