Mechanism of action: Mammalian target of rapamycin (mTOR) serine/threonine kinase (dual TORC1 and TORC2) inhibitor
AZD2014 is a potent (IC50 2.81nM), selective (inactive against 220 other kinases) inhibitor of mTOR kinase. It inhibited downstream targets of both mTORC1 (pS6 and p4EBP1) and mTORC2 (pAKT s473) in several in vitro models in a dose and time-dependent manner. In the MDA-MB-468 cell line, the IC50 for pAKT and pS6 were 78 and 210nM, respectively. AZD2014 induces dose-dependent tumour growth inhibition in xenograft models at well tolerated doses. In the MCF-7 ER+ breast model, significant tumour growth inhibition is achieved with continuous or intermittent dosing schedules of AZD2014, and efficacy is enhanced in combination with fulvestrant. Pharmacodynamic knockdown of pAKT, p4EBP1 and pS6 and increased apoptosis in tumour tissue is also seen in preclinical in vivo models.
Safety and tolerability
AZD2014 has been administered orally to solid tumour cancer patients in single doses up to 100mg and multiple doses up to 100mg BID. The most common adverse events were fatigue, nausea, mucositis, rash, constipation, vomiting, dyspnoea and cough (CTCAE grade 1-2) which improved in severity or resolved completely within 1 day up to 1 week after the drug was stopped or dose reduced and therefore a relationship with AZD2014 is likely.
Preclinical studies of up to 1 month duration have been performed.
At a dose of 50mg BID, AZD2014 reduced cytoplasmic pS6 (S235/236) immunohistochemistry staining in 8 of 10 evaluable paired tumour biopsies indicating mTORC1 activity. A reduction in cytoplasmic pS6 (S235/236) was observed in 8 out of 8 tumour biopsies obtained after 1 to 5 hours of therapy. In three of these tumours, phosphorylation of S6 was profoundly reduced, falling to below the limit of reliable detection following treatment. Phosphorylation of AKT (S473) was significantly inhibited in platelet rich plasma providing evidence for TORC2 inhibition in surrogate tissue.
Two patients, one each with pancreatic and breast cancer, have demonstrated partial response to AZD2014 monotherapy by RECIST, with four others having stable disease for >100 days.
Suitable for and exclusions
Preclinical reprotoxicology data are not available for this compound. The inclusion of women of child-bearing potential using highly effective contraception in trials of modest size and duration could be considered based on the risk benefit and in accordance with territory specific requirements.
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: