WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205669
Description: AZD5363, also known as Capivasertib, is an orally available inhibitor of the serine/threonine protein kinase AKT (protein kinase B) with potential antineoplastic activity. AKT inhibitor AZD5363 binds to and inhibits all AKT isoforms. Inhibition of AKT prevents the phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR signaling due to mutations in multiple signaling components.
MedKoo Cat#: 205669
Chemical Formula: C21H25ClN6O2
Exact Mass: 428.17275
Molecular Weight: 428.9152
Elemental Analysis: C, 58.81; H, 5.87; Cl, 8.27; N, 19.59; O, 7.46
Synonym: AZD5363; AZD-5363; AZD 5363; Capivasertib
IUPAC/Chemical Name: (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide
InChi Key: JDUBGYFRJFOXQC-KRWDZBQOSA-N
InChi Code: InChI=1S/C21H25ClN6O2/c22-15-3-1-14(2-4-15)17(6-12-29)27-20(30)21(23)7-10-28(11-8-21)19-16-5-9-24-18(16)25-13-26-19/h1-5,9,13,17,29H,6-8,10-12,23H2,(H,27,30)(H,24,25,26)/t17-/m0/s1
SMILES Code: O=C(C1(N)CCN(C2=C3C(NC=C3)=NC=N2)CC1)N[C@H](C4=CC=C(Cl)C=C4)CCO
AZD5363 is a novel pyrrolopyrimidine derived compound which inhibited all AKT isoforms with a potency of <10 nM, and inhibited phosphorylation of AKT substrates in cells with a potency of ~0.3 to 0.8 ÂµM. AZD5363 monotherapy inhibited the proliferation of 41/182 solid and hematologic tumor cell lines with a potency of <3 ÂµM. 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 EC50 ~0.1 ÂµM total plasma exposure), reversible increases in blood glucose concentrations and dose-dependent decreases in fluorodeoxyglucose (FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent inhibition of the growth 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. (source: Mol Cancer Ther molcanther.0824.2011)
1: Toren P, Kim S, Cordonnier T, Crafter C, Davies BR, Fazli L, Gleave ME, Zoubeidi A. Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical Models. Eur Urol. 2014 Aug 20. pii: S0302-2838(14)00748-9. doi: 10.1016/j.eururo.2014.08.006. [Epub ahead of print] PubMed PMID: 25151012.
2: Li J, Davies BR, Han S, Zhou M, Bai Y, Zhang J, Xu Y, Tang L, Wang H, Liu YJ, Yin X, Ji Q, Yu DH. The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere. J Transl Med. 2013 Oct 2;11:241. doi: 10.1186/1479-5876-11-241. PubMed PMID: 24088382; PubMed Central PMCID: PMC3850695.
3: Addie M, Ballard P, Buttar D, Crafter C, Currie G, Davies BR, Debreczeni J, Dry H, Dudley P, Greenwood R, Johnson PD, Kettle JG, Lane C, Lamont G, Leach A, Luke RW, Morris J, Ogilvie D, Page K, Pass M, Pearson S, Ruston L. Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin -4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J Med Chem. 2013 Mar 14;56(5):2059-73. doi: 10.1021/jm301762v. Epub 2013 Feb 26. PubMed PMID: 23394218.
4: Maynard J, Ricketts SA, Gendrin C, Dudley P, Davies BR. 2-Deoxy-2-[18F]fluoro-D-glucose positron emission tomography demonstrates target inhibition with the potential to predict anti-tumour activity following treatment with the AKT inhibitor AZD5363. Mol Imaging Biol. 2013 Aug;15(4):476-85. doi: 10.1007/s11307-013-0613-3. PubMed PMID: 23344784.
5: Lamoureux F, Thomas C, Crafter C, Kumano M, Zhang F, Davies BR, Gleave ME, Zoubeidi A. Blocked autophagy using lysosomotropic agents sensitizes resistant prostate tumor cells to the novel Akt inhibitor AZD5363. Clin Cancer Res. 2013 Feb 15;19(4):833-44. doi: 10.1158/1078-0432.CCR-12-3114. Epub 2012 Dec 20. PubMed PMID: 23258740.
6: 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. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol Cancer Ther. 2012 Apr;11(4):873-87. doi: 10.1158/1535-7163.MCT-11-0824-T. Epub 2012 Jan 31. PubMed PMID: 22294718.