Mechanism of action: AKT serine/threonine protein kinase (also known as protein kinase B alpha) inhibitor

Preclinical pharmacology

AZD5363 inhibits all AKT isoforms with a potency of <10nM, and inhibited phosphorylation of AKT substrates in cells with a potency of ~0.3 to 0.8µM.

AZD5363 monotherapy inhibited the proliferation of 41/182 solid and hematologic tumour cell lines with a potency of <3µM and 25/182 with a potency of <1µM. There is significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363, and between RAS mutations and resistance.

In xenograft studies in vivo AZD5363 significantly reduced phosphorylation of PRAS40, GSK3β and S6. Chronic oral dosing of AZD5363 causes dose-dependent inhibition of the growth of xenografts derived from various tumor types and AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib and trastuzumab in breast cancer xenografts. Dose-response at oral doses of 50 to 150mg/kg twice daily continuous dosing and intermittent dosing in the range of 100 to 200mg/kg twice daily, 4 days on, 3 days off have led to efficacy. Tolerability is variable in different strains, therefore a tolerability study is recommended.

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Suitable for and exclusions

Restricted to preclinical oncology studies (proposals) only.

Additional Information

Clinical trials for this compound

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Publications for this compound

Find out more about this compound by reading related publications:

Molecular Cancer Therapeutics

Preclinical Pharmacology of AZD5363, an Inhibitor of AKT: Pharmacodynamics, Antitumor Activity, and Correlation of Monotherapy Activity with Genetic Background

Gene information from the NCBi

This compound works on the following genes: