AZD8055
Preclinical pharmacology
AZD8055 is a potent, selective inhibitor of mTOR kinase, targeting both mTORC1 (rapamycin-sensitive) and mTORC2 (rapamycin insensitive) complexes. AZD8055 is specific against mTOR (IC50 value of 0.8 ± 0.2 nM using an immunoprecipitate of full length mTOR from HeLa cells in an ELISA-based kinase assay). AZD8055 was inactive in a counter screen against 260 kinases.
AZD8055 inhibited downstream targets of both mTORC1 (phosphorylation of S6 at serine 235/236) and mTORC2 (phosphorylation of AKT at serine 473) in several in vitro models in a dose- and time-dependent manner. Oral treatment of mice bearing U87-MG human glioma xenografts twice daily with 2.5, 5, and 10 mg/kg/day AZD8055 for 10-days resulted in a dose-dependent tumour growth inhibition of 33%, 48% and 77%, respectively. All doses were well tolerated. The growth inhibitory effect of once daily administration with 10 and 20 mg/kg of AZD8055 for 10-days was 57 and 85%, respectively. This tumour growth inhibitory effect was observed in a number of xenograft models tested in vivo. Furthermore, the antitumour activity in vivo was in good agreement with growth inhibition observed in cell lines in vitro.
Suitable for and exclusions
The use of AZD8055 is suitable for in vitro and ex vivo studies only.
Mechanism of Action
Mammalian target of rapamycin (mTOR) kinase (TORC1/2) inhibitor
Original Therapeutic Area
Oncology
CNS Penetrant
No
Route of administration
Oral
Modality
Small Molecule
Additional Information
1. Chresta CM., et al. (2010).
AZD8055 is a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res. 2010 Jan 1;70(1):288-98. doi: 10.1158/0008-5472.CAN-09-1751. Epub 2009 Dec 22. PMID: 20028854.