Mechanism of action: Src tyrosine kinase family inhibitor
Saracatinib (AZD0530) is a potent inhibitor of the Src family of tyrosine kinases (IC50 of 2.7 - 11nM for c-Src, Lck, c-YES, Lyn, Fyn, Fgr, and Blk) with high selectivity over other protein kinases involved in signal transduction. AZD0530 has sub-micromolar activity in a variety of cellular assays of human tumour cell proliferation and inhibits tumour growth in murine and rat allografts and xenografts at compound levels of ~2 x IC50 in plasma when dosed orally.
Safety and tolerability
AZD0530 has been administered orally to healthy human volunteers in single doses up to 1000mg and multiple doses up to 250mg QD for 14 days. Oncology patients have been dosed chronically at up to 175mg QD. Adverse events across various patient groups include: anaemia, nausea, anorexia, asthenia, pyrexia, vomiting, diarrhoea, and pneumonitis-type.
Preclinical toxicity studies (dog) of up to 9 months duration have been performed to support clinical dosing up to 12 months in duration. These reveal haematological changes and proliferative, hypertrophic and degenerative changes in multiple organs which were mild in severity and showed evidence of reversal. All changes were considered generally to be consistent with Src kinase inhibition.
Target coverage has been demonstrated in patients by decreased phosphorylation of focal adhesion kinase and paxilin in tumour biopsies. In healthy volunteers and patients, reduction in serum βCTX, a marker of bone resorption, was evident at doses of 125 and 175mg QD (125mg achieves plasma levels of ~5 x IC50 at Cmin steady state).
Suitable for and exclusions
The reproductive toxicology package indicates a risk of foetal toxicity. The inclusion of women of child-bearing potential would need to be assessed for any proposal based on the risk benefit and the use of appropriate highly effective contraception. AZD0530 is a moderately potent CYP3A4 inhibitor; concomitant administration of medicines that are metabolised by this route should be avoided.
AstraZeneca is not keen on pursuing AZD0530 for additional preclinical or clinical oncology indication research at this time.
Clinical trials for this compound
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Publications for this compound
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Gene information from the NCBi
This compound works on the following genes: