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|Ref Type||Journal Article|
|Authors||Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, Li J, Gao B, Ji Q, Maynard J, Ricketts SA, Cross D, Cosulich S, Chresta CC, Page K, Yates J, Lane C, Watson R, Luke R, Ogilvie D, Pass M|
|Title||Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 μmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ~ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2(+) breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Capivasertib||AZD5363|AZD 5363|AZD-5363||Akt Inhibitor (Pan) 21||Capivasertib (AZD5363) decreases PI3K/AKT/mTOR signaling by inhibition of AKT1, AKT2, and AKT3, potentially resulting in decreased cell proliferation (PMID: 22294718, PMID: 32532747, PMID: 32312891).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PIK3CA mutant||breast cancer||predicted - sensitive||Capivasertib||Preclinical||Actionable||In a preclinical study, AZD5363 inhibited growth in breast cancer cell lines and xenograft models expressing PIK3CA mutations (PMID: 22294718).||22294718|
|PTEN loss||Advanced Solid Tumor||sensitive||Capivasertib||Preclinical - Cell culture||Actionable||In a preclinical study, AZD5363 inhibited growth of various solid tumor cell culture models with loss of Pten (PMID: 22294718).||22294718|
|PTEN loss||renal carcinoma||sensitive||Capivasertib||Preclinical - Pdx||Actionable||In a preclinical study, AZD5363 inhibited growth of renal cancer Pdx models with Pten loss (PMID: 22294718).||22294718|
|PTEN inact mut||Advanced Solid Tumor||sensitive||Capivasertib||Preclinical - Cell culture||Actionable||In a preclinical study, AZD5363 inhibited growth of various solid tumor cell culture models with inactivating Pten mutations (PMID: 22294718).||22294718|