AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth.
The serine/threonine kinase AKT plays a pivotal role in signal transduction events involved in malignant transformation and chemoresistance and is an attractive target for the development of cancer therapeutics. Fragment-based lead discovery, combined with structure-based drug design, has recently identified AT7867 as a novel and potent inhibitor of both AKT and the downstream kinase p70 S6 kinase (p70S6K) and also of protein kinase A. This ATP-competitive small molecule potently inhibits both AKT and p70S6K activity at the cellular level, as measured by inhibition of GSK3beta and S6 ribosomal protein phosphorylation, and also causes growth inhibition in a range of human cancer cell lines as a single agent. Induction of apoptosis was detected by multiple methods in tumor cells following AT7867 treatment. Administration of AT7867 (90 mg/kg p.o. or 20 mg/kg i.p.) to athymic mice implanted with the PTEN-deficient U87MG human glioblastoma xenograft model caused inhibition of phosphorylation of downstream substrates of both AKT and p70S6K and induction of apoptosis, confirming the observations made in vitro. These doses of AT7867 also resulted in inhibition of human tumor growth in PTEN-deficient xenograft models. These data suggest that the novel strategy of AKT and p70S6K blockade may have therapeutic value and supports further evaluation of AT7867 as a single-agent anticancer strategy.
Grimshaw
Kyla M
KM
Astex Therapeutics, 436 Cambridge Science Park, Cambridge, UK.
Hunter
Lisa-Jane K
LJ
Yap
Timothy A
TA
Heaton
Simon P
SP
Walton
Mike I
MI
Woodhead
Steven J
SJ
Fazal
Lynsey
L
Reule
Matthias
M
Davies
Thomas G
TG
Seavers
Lisa C
LC
Lock
Victoria
V
Lyons
John F
JF
Thompson
Neil T
NT
Workman
Paul
P
Garrett
Michelle D
MD
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008954:Models, Biological; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
C551535:AT 7867; D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D051058:Oncogene Protein v-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa