Recent developments of small molecule PI3K/mTOR dual inhibitors

Mini-Reviews in Medicinal Chemistry

Volumn 13, Issue 14, 2013, Pages 2047-2059

  Liu, Yan Na ^a   Wan, Ren Zhong ^b   Liu, Zhao Peng ^a  

^a SHANDONG UNIVERSITY   (China)

^b SHANDONG AGRICULTURAL UNIVERSITY   (China)

Author keywords

Anticancer; Anticancer agents; Cancer; Dual PI3K mTOR kinase inhibitors; Kinase inhibitors; mTOR; PI3K; PI3K signaling pathway; PI3K ; PI3K Akt mTOR; SARs; Structure activity relationships

Indexed keywords

4 METHYLPYRIDOPYRIMIDINONE DERIVATIVE; APITOLISIB; ARYLPYRIMIDINE; BENZOFURAN 3 ONE INDOLE DERIVATIVE; BISMORPHOLINO 1,3,5 TRIAZINE DERIVATIVE; GSK 2126458; MAMMALIAN TARGET OF RAPAMYCIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MORPHOLINE DERIVATIVE; MORPHOLINO TRIAZINE DERIVATIVE; PF 04691502; PF 04979064; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PICTILISIB; PKI 179; PKI 587; PROTEIN KINASE B; PYRIDOPYRIMIDINONE DERIVATIVE; PYRIDYLSULFONAMIDE DERIVATIVE; PYRIMIDINONE DERIVATIVE; PYRIMIDINYLSUFONAMIDE; TRIAZINE DERIVATIVE; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; BREAST CANCER; CANCER INHIBITION; CELL CYCLE ARREST; CELL PROLIFERATION; DRUG BIOAVAILABILITY; DRUG POTENCY; ENZYME ACTIVITY; HUMAN; IC 50; LIVER CELL; NEOPLASM; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; STRUCTURE ACTIVITY RELATION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL SURVIVAL; HUMANS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; SMALL MOLECULE LIBRARIES; STRUCTURE-ACTIVITY RELATIONSHIP; TOR SERINE-THREONINE KINASES;

EID: 84892979090     PISSN: 13895575     EISSN: 18755607     Source Type: Journal    
DOI: 10.2174/13895575113136660105     Document Type: Review

References (36)

1. Liu, P.; Cheng, H.; Roberts, T. M.; Zhao, J. J. Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer. Nat. Rev. Drug Discovery, 2009, 8(8), 627-644.
2. Shuttleworth, S. J.; Silva, F. A.; Cecil, A. R.; Tomassi, C. D.; Hill, T. J.; Raynaud, F. I.; Clarke, P. A.; Workman, P. Progress in the preclinical discovery and clinical development of class I and dual class I/IV phosphoinositide 3-kinase (PI3K) inhibitors. Curr. Med. Chem., 2011, 18(18), 2686-2714.
3. Engelman, J. A.; Luo, J.; Cantley, L. C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet., 2006, 7(8), 606-619.
4. Wu, P.; Hu, Y. Small molecules targeting phosphoinositide 3-kinases. Med. Chem. Comm., 2012, 3(11), 1337-1355.
5. Sarbassov, D. D.; Ali, S. M.; Sabatini, D. M. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol., 2005, 17(6), 596-603.
6. Zaytseva, Y. Y.; Valentino, J. D.; Gulhati, P.; Mark Evers, B. mTOR inhibitors in cancer therapy. Cancer Lett., 2012, 319(1), 1-7.
7. Laplante, M.; Sabatini, D. M. mTOR signaling at a glance. J. Cell. Sci., 2009, 122(20), 3589-3594.
8. Engelman, J. A. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer, 2009, 9(8), 550-562.
9. Ciraolo, E.; Morello, F.; Hirsch, E. Present and future of PI3K pathway inhibition in cancer: perspectives and limitations. Curr. Med. Chem., 2011, 18(18), 2674-2685.
10. Shaw, R. J.; Cantley, L. C. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature, 2006, 441, 424-430.
11. Harris, T. E.; Lawrence Jr, J. C. TOR signaling. Sci. STKE, 2003, 212, re15.
12. Folkes, A. J.; Ahmadi, K.; Alderton, W. K.; Alix, S.; Baker, S. J.; Box, G.; Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S. A.; Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kugendradas, A.; Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.; Patel, S.; Pergl-Wilson, G. H.; Raynaud, F. I.; Robson, A.; Saghir, N.; Salphati, L.; Sohal, S.; Ultsch, M. H.; Valenti, M.; Wallweber, H. J. A.; Wan, N. C.; Wiesmann, C.; Workman, P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno [3, 2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem., 2008, 51(18), 5522-5532.
13. Sutherlin, D. P.; Sampath, D.; Berry, M.; Castanedo, G.; Chang, Z.; Chuckowree, I.; Dotson, J.; Folkes, A.; Friedman, L.; Goldsmith, R.; Heffron, T.; Lee, L.; Lesnick, J.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Prior, W. W.; Salphati, L.; Sideris, S.; Tian, Q.; Tsui, V.; Wan, N. C.; Wang, S.; Wiesmann, C.; Wong, S.; Zhu, B.-Y. Discovery of (thienopyrimidin-2-yl) aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer. J. Med. Chem., 2010, 53(3), 1086-1097.
14. Heffron, T. P.; Berry, M.; Castanedo, G.; Chang, C.; Chuckowree, I.; Dotson, J.; Folkes, A.; Gunzner, J.; Lesnick, J. D.; Lewis, C.; Mathieu, S.; Nonomiya, J.; Olivero, A.; Pang, J.; Peterson, D.; Salphati, L.; Sampath, D.; Sideris, S.; Sutherlin, D. P.; Tsui, V.; Wan, N. C.; Wang, S.; Wong, S.; Zhu, B.-Y. Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor. Bioorg. Med. Chem. Lett., 2010, 20(8), 2408-2411.
15. 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)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J. Med. Chem., 2011, 54(21), 7579-7587.
16. 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., 2009, 53(2), 798-810.
17. Venkatesan, A. M.; Dehnhardt, C. M.; Chen, Z.; Santos, E. D.; Dos Santos, O.; Bursavich, M.; Gilbert, A. M.; Ellingboe, J. W.; Ayral-Kaloustian, S.; Khafizova, G.; Brooijmans, N.; Mallon, R.; Hollander, I.; Feldberg, L.; Lucas, J.; Yu, K.; Gibbons, J.; Abraham, R.; Mansour, T. S. Novel imidazolopyrimidines as dual PI3-kinase/mTOR inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(2), 653-656.
18. 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. Med. Chem. Comm., 2010, 1(2), 139-144.
19. Yuan, J.; Mehta, P. P.; Yin, M.-J.; Sun, S.; Zou, A.; Chen, J.; Rafidi, K.; Feng, Z.; Nickel, J.; Engebretsen, J.; Hallin, J.; Blasina, A.; Zhang, E.; Nguyen, L.; Sun, M.; Vogt, P. K.; McHarg, A.; Cheng, H.; Christensen, J. G.; Kan, J. L. C.; Bagrodia, S. PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity. Mol. Cancer Ther., 2011, 10(11), 2189-2199.
20. Le, P. T.; Cheng, H.; Ninkovic, S.; Plewe, M.; Huang, X.; Wang, H.; Bagrodia, S.; Sun, S.; Knighton, D. R.; LaFleur Rogers, C. M.; Pannifer, A.; Greasley, S.; Dalvie, D.; Zhang, E. Design and synthesis of a novel pyrrolidinyl pyrido pyrimidinone derivative as a potent inhibitor of PI3K and mTOR. Bioorg. Med. Chem. Lett., 2012, 22(15), 5098-5103.
21. Liu, K. K. C.; Bagrodia, S.; Bailey, S.; Cheng, H.; Chen, H.; Gao, L.; Greasley, S.; Hoffman, J. E.; Hu, Q.; Johnson, T. O.; Knighton, D.; Liu, Z.; Marx, M. A.; Nambu, M. D.; Ninkovic, S.; Pascual, B.; Rafidi, K.; Rodgers, C. M. L.; Smith, G. L.; Sun, S.; Wang, H.; Yang, A.; Yuan, J.; Zou, A. 4-Methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(20), 6096-609.
22. Zask, A.; Kaplan, J.; Verheijen, J. C.; Richard, D. J.; Curran, K.; Brooijmans, N.; Bennett, E. M.; Toral-Barza, L.; Hollander, I.; Ayral-Kaloustian, S.; Yu, K. Morpholine derivatives greatly enhance the selectivity of mammalian target of rapamycin (mTOR) inhibitors. J. Med. Chem., 2009, 52(24), 7942-7945.
23. 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 inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor. J. Med. Chem., 2010, 53(6), 2636-2645.
24. 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(19), 5869-5873.
25. Dehnhardt, C. M.; Venkatesan, A. M.; Chen, Z.; Delos-Santos, E.; Ayral-Kaloustian, S.; Brooijmans, N.; Yu, K.; Hollander, I.; Feldberg, L.; Lucas, J.; Mallon, R. Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(16), 4773-4778.
26. 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(1), 39-43.
27. 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)/mammalian target of rapamycin (mTOR) dual inhibitors. J. Med. Chem., 2011, 54(6), 1789-1811.
28. Ali, I. U.; Schriml, L. M.; Dean, M. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity. J. Natl. Cancer Inst., 1999, 91(22), 1922-1932.
29. Eng, C. PTEN: one gene, many syndromes. Hum. Mutat., 2003, 22(3), 183-198.
30. Stec, M. M.; Andrews, K. L.; Booker, S. K.; Caenepeel, S.; Freeman, D. J.; Jiang, J.; Liao, H.; McCarter, J.; Mullady, E. L.; San 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(14), 5174-5184.
31. 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(13), 4735-4751.
32. Wurz, R. P.; Liu, L.; Yang, K.; Nishimura, N.; Bo, Y.; Pettus, L. H.; Caenepeel, S.; Freeman, D. J.; McCarter, J. D.; Mullady, E. L.; Miguel, T. S.; Wang, L.; Zhang, N.; Andrews, K. L.; Whittington, D. A.; Jiang, J.; Subramanian, R.; Hughes, P. E.; Norman, M. H. Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1, 3, 5-triazine sulfonamide scaffold. Bioorg. Med. Chem. Lett., 2012, 22(17), 5714-5720.
33. Bursavich, M. G.; Brooijmans, N.; Feldberg, L.; Hollander, I.; Kim, S.; Lombardi, S.; Park, K.; Mallon, R.; Gilbert, A. M. Novel benzofuran-3-one indole inhibitors of PI3 kinase-and the mammalian target of rapamycin: hit to lead studies. Bioorg. Med. Chem. Lett., 2010, 20(8), 2586-2590.
34. Zhang, N.; Ayral-Kaloustian, S.; Anderson, J. T.; Nguyen, T.; Das, S.; Venkatesan, A. M.; Brooijmans, N.; Lucas, J.; Yu, K.; Hollander, I.; Mallon, R. 5-Ureidobenzofuranone indoles as potent and efficacious inhibitors of PI3 kinase-and mTOR for the treatment of breast cancer. Bioorg. Med. Chem. Lett., 2010, 20(12), 3526-3529.
35. Liu, K. K. C.; Huang, X.; Bagrodia, S.; Chen, J. H.; Greasley, S.; Cheng, H.; Sun, S.; Knighton, D.; Rodgers, C.; Rafidi, K.; Zou, A.; Xiao, J.; Yan, S. Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(4), 1270-1274.
36. Cheng, H.; Li, C.; Bailey, S.; Baxi, S. M.; Goulet, L.; Guo, L.; Hoffman, J.; Jiang, Y.; Johnson, T. O.; Johnson, T. W.; Knighton, D. R.; Li, J.; Liu, K. K.-C.; Liu, Z.; Marx, M. A.; Walls, M.; Wells, P. A.; Yin, M.-J.; Zhu, J.; Zientek, M. Discovery of the highly potent PI3K/mTOR dual Inhibitor PF-04979064 through structurebased drug design. ACS Med. Chem. Lett., 2012, 4(1), 91-97.