PP242, a novel potent and selective mTOR inhibitor, can inhibit the active site of mTOR kinase in both mTORC1 and mTORC2 with IC50 of 8 nM.
The mammalian target of rapamycin (mTOR), a serine-threonine kinase, is present in two protein complexes, mTORC1 and mTORC2, that have distinct subunit composition, substrates and mechanisms of activation.
Treatment of PP242 was shown to lead to the death of certain mouse and human leukemia cells [1]. In primary AML cells and CD34+ progenitor cells, PP242 can inhibit the activity of mTOR and their downstream targets, therefore inducing cell apoptosis [2].
The component has also been used to study the role of COX-2 in vivo. In models of acute leukemia harboring the Philadelphia chromosome (Ph) translocation, PP242 can delay the onset of leukemia and augment the effects of front-line tyrosine kinase inhibitors more effectively, thereby suppressing the expansion of leukemia [1]. In addition, PP242 was shown to suppresse leukemia progression in a murine leukemia model which was driven by mutated FLT3 with constitutive activation of mTOR [2].
References:
1.Janes MR, Limon JJ, So L, Chen J, Lim RJ, Chavez MA, et al. Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor. Nat Med 2010,16:205-213.
2.Zeng Z, Shi YX, Tsao T, Qiu Y, Kornblau SM, Baggerly KA, et al. Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment. Blood 2012,120:2679-2689.
