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|Ref Type||Journal Article|
|Authors||Yap TA, Walton MI, Hunter LJ, Valenti M, de Haven Brandon A, Eve PD, Ruddle R, Heaton SP, Henley A, Pickard L, Vijayaraghavan G, Caldwell JJ, Thompson NT, Aherne W, Raynaud FI, Eccles SA, Workman P, Collins I, Garrett MD|
|Title||Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||AKT is frequently deregulated in cancer, making it an attractive anticancer drug target. CCT128930 is a novel ATP-competitive AKT inhibitor discovered using fragment- and structure-based approaches. It is a potent, advanced lead pyrrolopyrimidine compound exhibiting selectivity for AKT over PKA, achieved by targeting a single amino acid difference. CCT128930 exhibited marked antiproliferative activity and inhibited the phosphorylation of a range of AKT substrates in multiple tumor cell lines in vitro, consistent with AKT inhibition. CCT128930 caused a G(1) arrest in PTEN-null U87MG human glioblastoma cells, consistent with AKT pathway blockade. Pharmacokinetic studies established that potentially active concentrations of CCT128930 could be achieved in human tumor xenografts. Furthermore, CCT128930 also blocked the phosphorylation of several downstream AKT biomarkers in U87MG tumor xenografts, indicating AKT inhibition in vivo. Antitumor activity was observed with CCT128930 in U87MG and HER2-positive, PIK3CA-mutant BT474 human breast cancer xenografts, consistent with its pharmacokinetic and pharmacodynamic properties. A quantitative immunofluorescence assay to measure the phosphorylation and total protein expression of the AKT substrate PRAS40 in hair follicles is presented. Significant decreases in pThr246 PRAS40 occurred in CCT128930-treated mouse whisker follicles in vivo and human hair follicles treated ex vivo, with minimal changes in total PRAS40. In conclusion, CCT128930 is a novel, selective, and potent AKT inhibitor that blocks AKT activity in vitro and in vivo and induces marked antitumor responses. We have also developed a novel biomarker assay for the inhibition of AKT in human hair follicles, which is currently being used in 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|
|CCT128930||CCT-128930||Akt2 Inhibitor 2||CCT128930 is an ATP-competitive inhibitor of AKT2 with a lesser affinity for PKA and RPS6KB2. CCT128930 has antitumor activity in cells with activated PI3K-AKT-mTOR pathway (PMID: 21191045, PMID: 31608140).|
|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|
|PTEN loss||glioblastoma||sensitive||CCT128930||Preclinical - Cell line xenograft||Actionable||In preclinical studies, CCT128930 prevented tumor growth in a PTEN-null human glioblastoma cell line xenograft model (PMID: 21191045).||21191045|
|PIK3CA mutant||Her2-receptor positive breast cancer||sensitive||CCT128930||Preclinical - Cell line xenograft||Actionable||In a preclinical study, CCT128930 induced growth arrest and inhibited tumor growth in a xenograft model of a ERBB2 (HER2)-positive human breast cancer cell line harboring a PIK3CA mutation (PMID: 21191045).||21191045|