Page 5 of 6
ACS Medicinal Chemistry Letters
1
2
3
I PI3 kinase for the treatment of cancer. J. Med. Chem. 2008, 51,
5522–5532.
Science Foundation (2012M510380) and Beijing Postdoctoral
Research Foundation (2012ZZ-96).
12. Burger, M. T.; Pecchi, S.; Wagman, A.; Ni, Z. J.; Knapp, M.;
Hendrickson, T.; Atallah, G.; Pfister, K.; Zhang, Y.; Bartulis, S.;
Frazier, K.; Ng, S.; Smith, A.; Verhagen, J.; Haznedar, J.; Huh,
K.; Iwanowicz, E.; Xin, X.; Menezes, D.; Merritt, H.; Lee, I.;
Wiesmann, M.; Kaufman, S.; Crawford, K.; Chin, M.; Bussiere,
D.; Shoemaker, K.; Zaror, I.; Maira, S. M.; Voliva, C. F. Identiꢀ
fication of NVPꢀBKM120 as a potent, selective, orally bioavailꢀ
able Class I PI3 kinase inhibitor for treating cancer. ACS Med.
Chem. Lett. 2011, 2, 774–779.
4
5
6
7
8
9
ABBREVIATIONS
PI3K, phosphoinositide 3-kinase; mTOR, mammalian target
of rapamycin; PTEN, phosphotase and tensin homologue;
PAMPA, parallel artificial membrane permeability assay.
REFERENCES
1. Engelman, J. A.; Luo, J.; Cantley, L. C. The evolution of phosꢀ
phatidylinositol 3ꢀkinases as regulators of growth and metaboꢀ
lism. Nat. Rev. Genet. 2006, 7, 606ꢀ619.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
58&rank=3
2. Liu, P. X; Cheng, H. L.; Roberts, T. M.; Zhao, J. J. Targeting the
phosphoinositide 3ꢀkinase pathway in cancer. Nature Rev. Drug
Discov. 2009, 8, 627ꢀ644.
14. BEZꢀ235 was a positive control in our assays and its IC50s were
determined to be 6.2 nM and 11.5 nM for PI3Kα and mTOR reꢀ
spectively. See supplementary data for the assay protocols.
3. Sarbassov, D. D.; Ali, S. M.; Sabatini, D. M. Growing roles for
15. 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 3ꢀkinase (PI3K)/mammalian target of raꢀ
pamycin (mTOR) dual inhibitors: discovery and structureꢀ
activity relationships of a series of quinoline and quinoxaline deꢀ
rivatives. J. Med. Chem. 2011, 54, 4735–4751.
the mTOR pathway. Curr. Opin. Cell Biol. 2005, 17, 596ꢀ603.
4. Vivanco, I.; Sawyers, C. L. The phosphatidylinositol 3ꢀKinase
AKT pathway in human cancer. Nat. Rev. Cancer 2002, 2, 489ꢀ
501.
5. Strimpakos, A. S.; Karapanagiotou, E. M.; Wasif Saif, M.; Syriꢀ
gos, K. N. The role of mTOR in the management of solid tuꢀ
mors: an overview. Cancer Treat. Rev. 2009, 35, 148ꢀ159.
6. Harris, T. E.; Lawrence Jr., J. C. TOR signaling. Science’s
STKE, 2003, 2003, re15.
16. Adams, N. D.; Burgess, J. L.; Darcy, M. G.; Donatelli, C. A.;
Knight, S. D.; Newlander, K. A.; Ridgers, L.; Sarpong, M.;
Schmidt, S. J. Quinoline derivatives as PI3 kinase inhibitors.
WO2008144463, November 27, 2008.
7. Courtney, K. D.; Corcoran, R. B.; Engelman, J. A. The PI3K
pathway as drug target in human cancer. J Clin. Oncol. 2010, 28,
1075ꢀ1083.
17. Wissner, A.; Berger, D. M.; Boschelli, D. H.; Floyd, M. B. Jr.;
Greenberger, L. M.; Gruber, B. C.; Johnson, B. D.; Mamuya, N.;
Nilakantan, R.; Reich, M. F.; Shen, R.; Tsou, H. R.; Upeslacis,
E.; Wang, Y. F.; Wu, B.; Ye, F.; Zhang, N. 4ꢀAnilinoꢀ6,7ꢀ
dialkoxyquinolineꢀ3ꢀcarbonitrile inhibitors of epidermal growth
factor receptor kinase and their bioisosteric relationship to the 4ꢀ
anilinoꢀ6,7ꢀdialkoxyquinazoline inhibitors. J. Med. Chem. 2000,
43, 3244ꢀ3256.
8. Liu, K. K.; Zhu, J.; Smith, G. L.; Yin, M. J.; Bailey, S.; Chen, J.
H.; Hu, Q.; Huang, Q.; Li, C.; Li, Q. J.; Marx, M. A.; Paderes,
G.; Richardson, P. F.; Sach, N. W.; Walls, M.; Wells, P. A.;
Baxi, S.; Zou, A. Highly selective and potent thiophenes as PI3K
inhibitors with oral antitumor activity. ACS Med. Chem. Lett.
2011, 2, 809–813.
9. 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.; Sarpong, M. A.; Schmidt, S. J.; Van
Aller, G. S.; Carson, J. D.; Diamond, M. A.; Elkins, P. A.; Garꢀ
diner, C. M.; Garver, E.; Gilbert, S. A.; Gontarek, R. R.; Jackꢀ
son, J. R.; Kershner, K. L.; Luo, L.; Raha, K.; Sherk, C. S.;
Sung, C.; Sutton, D.; Tummino, P. J.; Wegrzyn, R. J.; Auger, K.
R.; Dhanak, D. Discovery of GSK2126458, a highly potent inꢀ
hibitor of PI3K and the mammalian target of rapamycin. ACS
Med. Chem. Lett. 2010, 1, 39–43.
18. Lin, S. W.; Han, F. B.; Liu, P.; Tao, J.; Zhong, X. C.; Liu, X. J.;
Yi, C. Q.; Xu, H. Identification of novel 7ꢀaminoꢀ5ꢀmethylꢀ1,6ꢀ
naphthyridinꢀ2(1H)ꢀone derivatives as potent PI3K/mTOR dual
inhibitors. Bioorg. Med. Chem. Lett. 2014, 24, 790–793.
19. Adams, N. D.; Burgess, J. L.; Darcy, M. G.; Donatelli, C. A.;
Knight, S. D.; Newlander, K. A.; Ridgers, L. H.; Schmidt, S. J.
Quinazoline
derivatives
as
PI3
kinase
inhibitors.
WO2008157191, December 24, 2008.
20. Morgentin, R.; Pasquet, G.; Boutron, P.; Jung, F.; Lamorlette,
M.; Maudet, M.; Ple, P. Strategic studies in the syntheses of
novel 6,7ꢀsubstituted quinolones and 7ꢀ or 6ꢀsubstituted 1,6ꢀ and
1,7ꢀnaphthyridones. Tetrahedron 2008, 64, 2772 – 2782.
10. Venkatesan, A. M.; Dehnhardt, C. M.; Delos Santos, E.; Chen,
Z.; Dos Santos, O.; AyralꢀKaloustian, 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(morpholinoꢀ1,3,5ꢀtriazine) derivatives: potent adenoꢀ
sine 5'ꢀtriphosphate competitive phosphatidylinositolꢀ3ꢀ
kinase/mammalian target of rapamycin inhibitors: discovery of
compound 26 (PKIꢀ587), a highly efficacious dual inhibitor. J.
Med. Chem. 2010, 53, 2636–2645.
21. Li, Q.; Woods, K. W.; Zhu, G. D.; Fischer, J. P.; Gong, J. C.; Li,
T. M.; Gandhi, V.; Thomas, S. A.; Packard, G.; Song, X. H.;
Abrams, J. N.; Diebold, R. Dinges, J.; Hutchins, C.; Stoll, V.;
Rosenberg, S. H.; Giranda, V. L. kinase inhibitors.
WO2003051366, June 26, 2003.
22. Han, F. B.; Lin, S. W.; Liu, P.; Tao, J.; Yi, C. Q.; Xu, H. Syntheꢀ
sis and structureꢀactivity relationships of PI3K/mTOR dual inꢀ
11. Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S.
J.; Box, G.; Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Ecꢀ
cles, S. A; Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kuꢀ
gendradas, A.; Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.;
Patel, S.; PerglꢀWilson, G. H.; Raynaud, F. I.; Robson, A.;
Saghir, N.; Salphati, L.; Sohal, S.; Ultsch, M. H.; Valenti, M.;
Wallweber, H. J.; Wan, N. C.;Wiesmann, C.; Workman, P.;
Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. The identifiꢀ
cation of 2ꢀ(1Hꢀindazolꢀ4ꢀyl)ꢀ6ꢀ(4ꢀmethanesulfonylꢀpiperazinꢀ1ꢀ
hibitors from
a
series of 2ꢀaminoꢀ4ꢀmethylpyrido[2,3ꢀ
d]pyrimidine derivatives. Bioorg. Med. Chem. Lett. 2014, 24,
4538–4541.
ylmethyl)ꢀ4ꢀmorpholinꢀ4ꢀylꢀthieno[3,2ꢀd]pyrimidine
0941) as a potent, selective, orally bioavailable inhibitor of class
(GDCꢀ
ACS Paragon Plus Environment