Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930

Molecular Cancer Therapeutics

Volumn 10, Issue 2, 2011, Pages 360-371

  Yap, Timothy A ^a   Walton, Mike I ^a   Hunter, Lisa Jane K ^a   Valenti, Melanie ^a   De Haven Brandon, Alexis ^a   Eve, Paul D ^a   Ruddle, Ruth ^a   Heaton, Simon P ^a   Henley, Alan ^a   Pickard, Lisa ^a   Vijayaraghavan, Gowri ^a   Caldwell, John J ^a   Thompson, Neil T ^b   Aherne, Wynne ^a   Raynaud, Florence I ^a   Eccles, Suzanne A ^a   Workman, Paul ^a   Collins, Ian ^a   Garrett, Michelle D ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

^b ASTEX PHARMACEUTICALS   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CCT 128930; EPIDERMAL GROWTH FACTOR RECEPTOR 2; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN KINASE B INHIBITOR; PYRROLOPYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CANCER; CELL CYCLE G1 PHASE; CONTROLLED STUDY; FEMALE; GLIOBLASTOMA; HAIR FOLLICLE; HUMAN; IMMUNOFLUORESCENCE TEST; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; TUMOR CELL LINE; TUMOR XENOGRAFT;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; ANTINEOPLASTIC AGENTS; BIOMARKERS, PHARMACOLOGICAL; CELL CYCLE; CELL LINE, TUMOR; CELL PROLIFERATION; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HAIR FOLLICLE; HCT116 CELLS; HUMANS; MALE; MICE; MICE, INBRED BALB C; MICE, NUDE; NEOPLASMS; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; PYRIMIDINES; PYRROLES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 79951815611     PISSN: 15357163     EISSN: 15388514     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-10-0760     Document Type: Article

References (46)

1. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-62.
2. Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 2008;8:393-412.
3. Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, et al. Role of translocation in the activation and function of protein kinase B. J Biol Chem 1997;272:31515-24. (Pubitemid 28013293)
4. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997;7:261-9. (Pubitemid 27176852)
5. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-101. (Pubitemid 40262113)
6. Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J 2001;359:1-16. (Pubitemid 32939202)
7. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857-68. (Pubitemid 29165088)
8. Mamane Y, Petroulakis E, LeBacquer O, Sonenberg N. mTOR, translation initiation and cancer. Oncogene 2006;25:6416-22. (Pubitemid 44582285)
9. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28:1075-83.
10. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81. (Pubitemid 46849157)
11. Donald A,McHardy T, Rowlands MG, Hunter LJ, Davies TG, Berdini V, et al. Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design. J Med Chem 2007;50: 2289-92. (Pubitemid 46799239)
12. Caldwell JJ, Davies TG, Donald A, McHardy T, Rowlands MG, Aherne GW, et al. Identification of 4-(4-aminopiperidin-1-yl)-7Hpyrrolo[ 2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration. J Med Chem 2008; 51:2147-57.
13. Davies TG, Verdonk ML, Graham B, Saalau-Bethell S, Hamlett CC, McHardy T, et al. A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. J Mol Biol 2007;367:882-94. (Pubitemid 46335912)
14. Workman P, Collins I. Probing the probes: fitness factors for small molecule tools. Chem Biol 2010;17:561-77.
15. Sarker D, Workman P. Pharmacodynamic biomarkers for molecular cancer therapeutics. Adv Cancer Res 2007;96:213-68.
16. Tan DS, Thomas GV, Garrett MD, Banerji U, de Bono JS, Kaye SB, et al. Biomarker-driven early clinical trials in oncology: a paradigm shift in drug development. Cancer J 2009;15:406-20.
17. Workman P. Auditing the pharmacological accounts for Hsp90 molecular chaperone inhibitors: unfolding the relationship between pharmacokinetics and pharmacodynamics. Mol Cancer Ther 2003; 2:131-8.
18. Camidge DR, Randall KR, Foster JR, Sadler CJ, Wright JA, Soames AR, et al. Plucked human hair as a tissue in which to assess pharmacodynamic end points during drug development studies. Br J Cancer 2005;92:1837-41. (Pubitemid 40826129)
19. Williams R, Baker AF, Ihle NT, Winkler AR, Kirkpatrick L, Powis G. The skin and hair as surrogate tissues for measuring the target effect of inhibitors of phosphoinositide-3-kinase signaling. Cancer Chemother Pharmacol 2006;58:444-50. (Pubitemid 43999792)
20. Yap TA, Papadopoulos K, Fearen I, Carpenter C, Delgado L, Taylor A, et al. First dose-finding study in cancer patients (pts) of a potent, selective, allosteric AKT inhibitor MK2206 (MK), incorporating pharmacodynamic (PD) and predictive biomarkers and showing profound pathway blockade. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia, PA: AACR; 2010. Abstract 27.
21. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 1990;82:1107-12. (Pubitemid 20213250)
22. Walton MI, Eve PD, Hayes A, Valenti M, De Haven Brandon A, Box G, et al. The preclinical pharmacology and therapeutic activity of the novel CHK1 inhibitor SAR-020106. Mol Cancer Ther 2010;9:89-100.
23. Wilson GD. Analysis of DNA - Measurements of Cell Kinetics by the Bromodeoxyuridine/Antibromodeoxyuridine Method. In: Omerod MG, Editor. Flow cytometry - A practical approach. Oxford: IRL Press; 1994, pp. 137-56.
24. Workman P, Aboagye EO, Balkwill F, Balmain A, Bruder G, Chaplin DJ, et al. Guidelines for the welfare and use of animals in cancer research. Br J Cancer 2010;102:1555-77.
25. Gowan SM, Hardcastle A, Hallsworth AE, Valenti MR, Hunter LJ, de Haven Brandon AK, et al. Application of meso scale technology for the measurement of phosphoproteins in human tumor xenografts. Assay Drug Dev Technol 2007;5:391-401. (Pubitemid 47067884)
26. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248-54.
27. McHardy T, Caldwell JJ, Cheung KM, Hunter LJ, Taylor K, Rowlands M, et al. Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl) piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt). J Med Chem 2010;53:2239-49.
28. Sanger Institute Cosmic database. Available from: http://www.sanger.ac. uk/genetics/CGP/cosmic/.
29. Gao N, Zhang Z, Jiang BH, Shi X. Role of PI3K/AKT/mTOR signaling in the cell cycle progression of human prostate cancer. Biochem Biophys Res Commun 2003;310:1124-32. (Pubitemid 37237653)
30. 1 CDKs in choroidal melanoma cells. FEBS Lett 1998;422:385-90.
31. Guillard S, Clarke PA, Te Poele R, Mohri Z, Bjerke L, Valenti M, et al. Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma. Cell Cycle 2009;8:443-53.
32. Luo Y, Shoemaker AR, Liu X, Mohri Z, Bjerke L, Valenti M, et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol Cancer Ther 2005;4:977-86. (Pubitemid 40909080)
33. Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 2008; 68:2366-74. (Pubitemid 351521811)
34. Lu W, Defeo-Jones D, Davis LJ, Hang G, Tammam J, Hatch H, et al. In vitro and in vivo antitumor activities of MK-2206, a new allosteric Akt inhibitor In: Proceedings of the 100th Annual Meeting of the American Association for Cancer Research ; 2009 Apr18-22; San Diego, CA: AACR; 2009. Abstract 3714.
35. Kondapaka SB, Singh SS, Dasmahapatra GP, Sausville EA, Roy KK. Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation. Mol Cancer Ther 2003;2:1093-103.
36. Han EK, Leverson JD, McGonigal T, Eberwein DJ, Knick VB, Lansing TJ, et al. Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. Oncogene 2007;26:5655-61. (Pubitemid 47267835)
37. Okuzumi T, Fiedler D, Zhang C, Gray DC, Aizenstein B, Hoffman R, et al. Inhibitor hijacking of Akt activation. Nat Chem Biol 2009; 5:484-93.
38. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S, Rebholz H, et al. The TSC1-2 tumor suppressor controls insulin- PI3K signaling via regulation of IRS proteins. J Cell Biol 2004; 166:213-23. (Pubitemid 38988774)
39. Gao N, Flynn DC, Zhang Z, Zhong XS, Walker V, Liu KJ, et al. G1 cell cycle progression and the expression of G1 cyclins are regulated by PI3K/AKT/mTOR/p70S6K1 signaling in human ovarian cancer cells. Am J Physiol Cell Physiol 2004;287:C281-91.
40. Raynaud FI, Eccles S, Clarke PA, Hayes A, Nutley B, Alix S, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res 2007;67:5840-50. (Pubitemid 46985018)
41. Fan QW, Knight ZA, Goldenberg DD, Yu W, Mostov KE, Stokoe D, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell 2006;9:341-9. (Pubitemid 43668732)
42. Workman P. Challenges of PK/PD measurements in modern drug development. Eur J Cancer 2002;38:2189-93. (Pubitemid 35223253)
43. Workman P. How much gets there and what does it do? The need for better pharmacokinetic and pharmacodynamic endpoints in contemporary drug discovery and development. Curr Pharm Des 2003;9: 891-902. (Pubitemid 36367612)
44. Yap TA, Sandhu SK, Workman P, de Bono JS. Envisioning the future of early anticancer drug development. Nat Rev Cancer 2010;10:514-23.
45. Camidge DR, Pemberton M, Growcott J, Barrass NC, Foster JR, Febbraro S, et al. A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers. Cancer Chemother Pharmacol 2007;60:479-88. (Pubitemid 47084256)
46. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007;9:316-23. (Pubitemid 46344611)