P-6666 PP242, Free Base, >99%

Synonyms : [Torkinib]

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  • M.W. 308.34
  • C16H16N6O
  • [1092351-67-1]

Storage: Store at or below -20 ºC. Solubility: Soluble in DMSO. Disposal: A.

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  • PP242 is an inhibitor at the kinase domain of the mammalian target of rapamycin (mTOR), which is a Ser/Thr kinase and a cell growth controller.
  • PP242 inhibits mTORC1 more effectively than rapamycin. Unlike rapamycin, PP242 inhibits both mTORC1 and mTORC2. PP242 blocks the phosphorylation of Akt at S473 and prevents its activation. PP242 inhibits the proliferation of primary cells more efficiently than rapamycin. Unlike rapamycin, it also inhibits cap-dependent translation under conditions. Feldman, M.E., et al. "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2." PLoS Biol. 7: 371-383 (2009).
  • PP242, but not rapamycin, induced death of mouse and human leukemia cells in vitro. In vivo, PP242 delayed leukemia onset and enhanced the effects of the front-line tyrosine kinase inhibitors more effectively than does rapamycin. However, PP242 had much weaker effects than rapamycin on the proliferation of normal lymphocytes. Janes, M.R., et al. "Effective and selective targeting of leukemia cells using a TORC1/2 kinase inhibitor." Nat. Med. 16: 205-213 (2010).
  • PP242 inhibited basal serum- and glucocorticoid-inducible protein kinase 1 (SGK1) activity and prevented insulin- and dexamethasone-induced SGK1 activation, possibly by suppressing TORC1/2. It inhibited basal Na+ absorption modestly and insulin/dexamethasone-induced Na+ transport substantially. Mansley, M.K. and Wilson, S.M. "Dysregulation of epithelial Na+ absorption induced by inhibition of the kinases TORC1 and TORC2." Br. J. Pharmacol. 161: 1778-1792 (2010).
  • PP242 inhibited growth and induced apoptosis of multiple myeloma (MM) cells more effectively than rapamycin. PP242 was an effective inhibitor of primary MM cells in vitro and growth of 8226 cells in mice. Combining bortezomib with PP242 resulted in synergistic anti-MM effects. Hoang, B., et al. "Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor." Blood 116: 4560-4568 (2010).
  • PP242 significantly augmented histone deacetylase inhibitor-induced apoptosis in hepatocellular carcinoma cells. Shao, H., et al. "Dual targeting of mTORC1/C2 complexes enhances histone deacetylase inhibitor-mediated anti-tumor efficacy in primary HCC cancer in vitro and in vivo." J. Hepatol. Aug 8 (2011) [Epub ahead of print].
  • In the presence of 100 µM ATP, PP242 inhibits both mTORC1 and mTORC2, with IC50 values of 0.03 and 0.058 µM, respectively. PP242 showed the following IC50 values for inhibition of 22 kinases:
  • In the presence of 100 µM ATP, PP242 inhibits both mTORC1 and mTORC2, with IC50 values of 0.03 and 0.058 µM, respectively. PP242 showed the following IC50 values for inhibition of 22 kinases: In vitro IC50 values for inhibition of 22 kinases by PP242 Kinase Kinase Category Form* [ATP], µM IC50 µM Ref. Abl Tyrosine ? 10 3.6 1 DNA-PK Ser/Thr PP 10 0.41 1 EGFR Tyrosine CD 10 4.4 1 EphB4 Tyrosine CD 10 3.4 1 Hck Tyrosine PP 10 1.2 1 JAK2 Tyrosine ** 10 0.11 2 mTOR Ser/Thr *** 10 0.01 1 mTOR1 Ser/Thr ? 100 0.03 2 mTOR2 Ser/Thr ? 100 0.06 2 p110α Lipid PP 10 2 1 p110β Lipid PP 10 2.2 1 p110γ Lipid PP 10 1.3 1 p110δ Lipid PP 10 0.1 1 PDGFRβ Tyrosine CD 10 0.41 1 PDK1 Ser/Thr PP 10 >10 2 PKCα Ser/Thr PP 10 0.05 2 PKCβ I Ser/Thr PP 10 0.2 2 PKCβ II Ser/Thr PP 10 0.19 2 RET Tyrosine CD 10 0.22 2 Src Tyrosine PP 10 1.4 1 Src(T338I) Tyrosine PP 10 5.1 1 VEGFR2 Tyrosine CD 10 1.5 1 * Form of the enzyme: "PP" = purified protein; "CD" = cytoplasmic domain ** Amino acid residues 809-1141 *** Amino acid residues 1360-2549 In the two references below, which have the same corresponding author, conflicting IC50 values were given for p110γ (IC50 = 1.3 or 0.1 µM) and p110δ (IC50 = 1.3 or 0.1 µM), respectively. We have reviewed all the relevant data in the articles and we conclude that the values in the above table are the correct values. We also note that reference #1 below contains conflicting statements about the kinase forms used in the table above. "Materials and Methods" in that reference states that "For IC50 value determinations, purified kinase domains were incubated with inhibitors . . .", whereas Supplementary Table 1 states that "All IC50 values were measured against purified kinases . . ." After thorough review of all relevant data in the two references below, in addition to extensive discussions with technical service at Invitrogen, we conclude that the forms of the kinases indicated in column 3 of the table above are correct. We were unable to make determinations in the case of three of the kinases, as indicated by question marks in the table. 1. Feldman, M.E., et al. "Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2." PLoS Biol. 7: 371-383 (2009). 2. Apsel, B., et al. "Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases." Nat. Chem. Biol. 4: 691-699 (2008).
  • Manual docking analyses demonstrated that PP242 was able to fit into the TOR model. Sturgill, T.W. and Hall M.N. "Activating mutations in TOR are in similar structures as oncogenic mutations in PI3KCalpha." ACS Chem. Biol. 4: 999-1015 (2009).
  • NOTE: the term "torkinib" has been used to specify PP242 itself, but is also now in use to generically describe compounds that inhibit mTOR at the kinase domain.
  • Sold for laboratory or manufacturing purposes only; not for human, veterinary, food, or household use.
  • This product is offered for R&D use in accordance with (i) 35 USC 271(e)+A13(1) in the U.S.; (ii) Section 69.1 of Japanese Patent Law in Japan; (iii) Section 11, No. 2 of the German Patent Act of 1981 in Germany; (iv) Section 60, Paragraph 5b of the U.K. Patents Act of 1977 in the U.K.; (v) Sections 55.2(1) and 55.2(6) and other common law exemptions of Canadian patent law; (vi) Section 68B of the Patents Act of 1953 in New Zealand together with the amendment of same by the Statutes Amendment Bill of 2002; (vii) such related legislation and/or case law as may be or become applicable in the aforementioned countries; and (viii) such similar laws and rules as may apply in various other countries.
  • Not available in some countries; not available to some institutions; not available for some uses.