title: Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background.
abstract: 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.
authors.affiliation: Oncology iMED, AstraZeneca, Cheshire, UK. Barry.Davies@astrazeneca.com
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
authors.forename: Hannah
authors.initials: H
authors.lastname: Greenwood
authors.forename: Phillippa
authors.initials: P
authors.lastname: Dudley
authors.forename: Claire
authors.initials: C
authors.lastname: Crafter
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Yu
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Beirong
authors.initials: B
authors.lastname: Gao
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
authors.forename: Juliana
authors.initials: J
authors.lastname: Maynard
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Ricketts
authors.forename: Darren
authors.initials: D
authors.lastname: Cross
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.forename: Christine C
authors.initials: CC
authors.lastname: Chresta
authors.forename: Ken
authors.initials: K
authors.lastname: Page
authors.forename: James
authors.initials: J
authors.lastname: Yates
authors.forename: Clare
authors.initials: C
authors.lastname: Lane
authors.forename: Rebecca
authors.initials: R
authors.lastname: Watson
authors.forename: Richard
authors.initials: R
authors.lastname: Luke
authors.forename: Donald
authors.initials: D
authors.lastname: Ogilvie
authors.forename: Martin
authors.initials: M
authors.lastname: Pass
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; D051057:Proto-Oncogene Proteins c-akt; C575618:capivasertib