ACS Medicinal Chemistry Letters
Letter
(3) Engelman, J. A. Targeting PI3K signaling in cancer:
opportunities, challenges and limitations. Nat. Rev. Cancer 2009, 9,
550−562.
(4) Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3-kinase
AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489−501.
(5) Manning, B. D.; Cantley, L. C. Akt/PKB signaling: navigating
downstream. Cell 2007, 129, 1261−1274.
(6) Guertin, D. A.; Sabatini, D. M. Defining the role of mTOR in
cancer. Cancer Cell 2007, 12, 9−22.
(7) Hennessy, B. T.; Smith, D. L.; Ram, P. T.; Lu, Y.; Mills, G. B.
Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev.
Drug Discovery 2005, 4, 988−1004.
(8) Fan, Q. W.; Knight, Z. A.; Goldenberg, D. D.; Yu, W.; Mostov, K.
E.; Stokoe, D.; Shokat, K. M.; Weiss, W. A. A dual PI3 kinase/mTOR
inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006, 9,
341−349.
(9) Dehnhardt, C. M.; Venkatesan, A. M.; Delos Santos, E.; Chen, Z.;
Santos, O.; Ayral-Kaloustian, S.; Brooijmans, N.; Mallon, R.;
Hollander, I.; Feldberg, L.; Lucas, J.; Chaudhary, I.; Yu, K.; Gibbons,
J.; Abraham, R.; Mansour, T. S. Lead optimization of N-3-substituted
7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/
mammalian target of rapamycin inhibitors: discovery of PKI-402. J.
Med. Chem. 2010, 53, 798−810.
(10) Maira, S. M.; Stauffer, F.; Brueggen, J.; Furet, P.; Schnell, C.;
Fritsch, C.; Brachmann, S.; Chene, P.; De Pover, A.; Schoemaker, K.;
Fabbro, D.; Gabriel, D.; Simonen, M.; Murphy, L.; Finan, P.; Sellers,
W.; Garcia-Echeverria, C. Identification and characterization of NVP-
BEZ235, a new orally available dual phosphatidylinositol 3-kinase/
mammalian target of rapamycin inhibitor with potent in vivo
antitumor activity. Mol. Cancer Ther. 2008, 7, 1851−1863.
(11) D'Angelo, N. D.; Kim, T.-S.; Andrews, K.; Booker, S. K.;
Caenepeel, S.; Chen, K.; D'Amico, D.; Freeman, D.; Jiang, J.; Liu, L.;
McCarter, J. D.; San Miguel, T.; Mullady, E. L.; Schrag, M.;
Subramanian, R.; Tang, J.; Wahl, R. C.; Wang, L.; Whittington, D.
A.; Wu, T.; Xi, N.; Xu, Y.; Yakowec, P.; Yang, K.; Zalameda, L. P.;
Zhang, N.; Hughes, P.; Norman, M. H. Discovery and optimization of
a series of benzothiazole phosphoinositide 3-kinase (PI3K)/mamma-
lian target of rapamycin (mTOR) dual inhibitors. J. Med. Chem. 2011,
54, 1789−1811.
Miguel, T.; Subramanian, R.; Tamayo, N.; Wang, L.; Yang, K.;
Zalameda, L. P.; Zhang, N.; Hughes, P. E.; Norman, M. H. Structure
activity relationships of phosphoinositide 3-kinase (PI3K)/mammalian
target of rapamycin (mTOR) dual inhibitors: investigations of various
6,5-heterocycles to improve metabolic stability. J. Med. Chem. 2011,
54, 5174−5184.
(17) Sutherlin, D. P.; Bao, L.; Berry, M.; Castanedo, G.; Chuckowree,
I.; Dotson, J.; Folks, A.; Friedman, L.; Goldsmith, R.; Gunzner, J.;
Heffron, T.; Lesnick, J.; Lewis, C.; Mathieu, S.; Murray, J.; Nonomiya,
J.; Pang, J.; Pegg, N.; Prior, W. W.; Rouge, L.; Salphati, L.; Sampath,
D.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wei, B.; Wiesmann, C.;
Wu, P.; Zhu, B.-Y.; Olivero, A. Discovery of a potent, selective, and
orally available class I phosphatidylinositol 3-kinase (PI3K)/mamma-
lian target of rapamycin (mTOR) kinase Inhibitor (GDC-0980) for
the treatment of cancer. J. Med. Chem. 2011, 54, 7579−7587.
(18) Nishimura, N.; Siegmund, A.; Liu, L.; Yang, K.; Bryan, M. C.;
Andrews, K. L.; Bo, Y.; Booker, S. K.; Caenepeel, S.; Freeman, D.;
Liao, H.; McCarter, J.; Mullady, E. L.; San Miguel, T.; Subramanian,
R.; Tamayo, N.; Wang, L.; Whittington, D. A.; Zalameda, L.; Zhang,
N.; Hughes, P. E.; Norman, M. H. Phospshoinositide 3-kinase
(PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors:
discovery and structure activity relationships of a series of quinoline
and quinoxaline derivatives. J. Med. Chem. 2011, 54, 4735−4751.
(19) The figures were prepared by Pymol and Maestro packages, see:
(a) The PyMOL Molecular Graphics System, version 1.8.6.2;
Schrodinger. (b) Maestro, release 2017-3; Schrodinger, LLC: New
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(20) The activities of GKS2126458 against PI3Kα and mTOR are
0.55 and 0.68 nM, respectively.
(12) Venkatesan, A. M.; Dehnhardt, C. M.; Delos Santos, E.; Chen,
Z.; Dos Santos, O.; Ayral-Kaloustian, S.; Khafizova, g.; Brooijmans, N.;
Mallon, R.; Hollander, I.; Feldberg, L.; Lucas, J.; Yu, K.; Gibbons, J.;
Abraham, R. T.; Chaudhary, I.; Mansour, T. S. Bis(morpholino-1,3,5-
triazine) derivatives: potent adenosine 5′-triphosphate competitive
phosphatidylinositol-3-kinase/mammalian target of rapamycin inhib-
itors: discovery of compound 26 (PKI-587), a highly efficacious dual
inhibitor. J. Med. Chem. 2010, 53, 2636−2645.
(13) Venkatesan, A. M.; Chen, Z.; Santos, O. D.; Dehnhardt, C.;
Santos, E. D.; Ayral-Kaloustian, S.; Mallon, R.; Hollander, I.; Feldberg,
L.; Lucas, J.; Yu, K.; Chaudhary, I.; Mansour, T. S. PKI-179: An orally
efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian
target of rapamycin (mTOR) inhibitor. Bioorg. Med. Chem. Lett.
2010, 20, 5869−5873.
(14) Knight, S. D.; Adams, N. D.; Burgess, J. L.; Chaudhari, A. M.;
Darcy, M. G.; Donatelli, C. A.; Luengo, J. I.; Newlander, K. A.; Parrish,
C. A.; Ridgers, L. H.; Sarpong, M. A.; Schmidt, S. J.; Van Aller, G. S.;
Carson, J. D.; Diamond, M. A.; Elkins, P. A.; Gardiner, C. M.; Garver,
E.; Gilbert, S. A.; Gontarek, R. R.; Jackson, J. R.; Kershner, K. L.; Luo,
L.; Raha, K.; Sherk, C. S.; Sung, C.-M.; Sutton, D.; Tummino, P. J.;
Wegrzyn, R. J.; Auger, K. R.; Dhanak, D. Discovery of GSK2126458, a
highly potent inhibitor of PI3K and the mammalian target of
rapamycin. ACS Med. Chem. Lett. 2010, 1, 39−43.
(15) Cheng, H.; Bagrodia, S.; Bailey, S.; Edwards, M.; Hoffman, J.;
Hu, Q.; Kania, R.; Knighton, D. R.; Marx, M. A.; Ninkovic, S.; Sun, S.;
Zhang, E. Discovery of the highly potent PI3K/mTOR dual inhibitor
PF-04691502 through structure based drug design. MedChemComm
2010, 1, 139−144.
(16) Stec, M. M.; Andrews, K. L.; Booker, S. K.; Caenepeel, S.;
Freeman, D. J.; Jiang, J.; Liao, H.; McCarter, J.; Mullady, E. L.; San
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