Identification of GNE-477, a potent and efficacious dual PI3K/mTOR inhibitor

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 8, 2010, Pages 2408-2411

  Heffron, Timothy P ^a   Berry, Megan ^a   Castanedo, Georgette ^a   Chang, Christine ^a   Chuckowree, Irina ^b   Dotson, Jennafer ^a   Folkes, Adrian ^b   Gunzner, Janet ^a   Lesnick, John D ^a   Lewis, Cristina ^a   Mathieu, Simon ^a   Nonomiya, Jim ^a   Olivero, Alan ^a   Pang, Jodie ^a   Peterson, David ^a   Salphati, Laurent ^a   Sampath, Deepak ^a   Sideris, Steve ^a   Sutherlin, Daniel P ^a   Tsui, Vickie ^a   Wan, Nan Chi ^b   Wang, Shumei ^a   Wong, Susan ^a   Zhu, Bing yan ^a   more..

^a GENENTECH INC   (United States)

^b Piramed Pharma   (United Kingdom)

Author keywords

Kinase inhibitors; mTOR; PI3K

Indexed keywords

GNE 477; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; UNCLASSIFIED DRUG;

ADDITION REACTION; ANIMAL EXPERIMENT; ARTICLE; CONTROLLED STUDY; DOG; DRUG DOSE COMPARISON; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; RAT;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; DOGS; ENZYME INHIBITORS; FEMALE; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; MICE; PROTEIN-SERINE-THREONINE KINASES; PYRIMIDINES; RATS; THIOPHENES;

EID: 77950048995     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.03.046     Document Type: Article

References (21)

1. Vivanco I., and Sawyers C.L. Nat. Rev. Cancer 2 (2002) 489
2. Cantley L.C. Science 296 (2002) 1655
3. Guertin D.A., and Sabatini D.M. Cancer Cell 12 (2007) 9
4. Fasolo A., and Sessa C. Expert Opin. Invest. Drugs 17 (2008) 1717
5. Bellacosa A., Kumar C.C., Di Cristofano A., et al. Adv. Cancer Res. 94 (2005) 29
6. Ihle N.T., and Powis G. Mol. Cancer Ther. 8 (2009) 1
7. Maira S.-M., Stauffer F., Schnell C., and García-Echeverría C. Biochem. Soc. Trans. 37 (2009) 265
8. 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 P., Zvelebil M.J., and Shuttleworth S.J. J. Med. Chem. 51 (2008) 5522
9. MCF7.1 is a HER2 transfected clone of the original MCF7 cell line (ATCC, Manassas, VA) that expresses elevated levels of HER2 and contains the PI3K E545K activating mutation found in the parental line.
10. 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., and Zhu B.-Y. J. Med. Chem. 53 (2010) 1086
11. 50 for the analog of 2 in which the aminopyrimidine is replaced by the 4-indazole present in GDC-0941 is 40 nM. For a description of these inhibitors and their key interactions within the binding site, and detailed methods, see Ref. 4.
12. Yalkowsky S.H., and Valvani S.C. J. Pharm. Sci. 69 (1980) 912
13. Quantum mechanics calculations suggest that the lowest energy conformation of 6 positions the aryl sulfone 30° out of plane, but with the co-planar conformation accessible at just 0.4 kcal/mol penalty.
14. Quantum mechanical energies were computed using Jaguar version 7.5 by Schrodinger (Schrodinger, Inc.), at the 6-31G**+/B3LYP level of theory. The 'Relaxed Coordinate Scan' method was used to vary the dihedral angle between the thiophene/methylthiophene and the aryl ring between 0° and 90° at 30° intervals.
15. -6 cm/s in a permeability assay using MDCK cells.
16. 50 using this cell line was 174 nM.
17. Each group, including vehicle, exhibited similar and acceptable weight loss of less than 10% relative to starting mass.
18. Bayliss, T.; Chuchowree, I.; Folkes, A.; Oxenford, S.; Wan, N. C.; Castanedo, G.; Goldsmith, R.; Gunzner, J.; Heffron, T.; Mathieu, S.; Olivero, A.; Staben, S.; Sutherlin, D. P.; Zhu, B.-Y. WO2008/070740 A1.
19. Castanedo, G.; Dotson, J.; Goldsmith, R.; Gunzner, J.; Heffron, T.; Mathieu, S.; Olivero, A.; Staben, S.; Sutherlin, D. P.; Tsui, V.; Wang, S.; Zhu, B.-Y.; Bayliss, T.; Chuckowree, I.; Folkes, A.; Wan, N. C. WO2008/073785 A2.
20. Denton S.M., and Wood A. Synlett (1999) 55
21. 50's of 4, 86, 6, and 15 nM, respectively.