WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205669
CAS#: 1143532-39-1
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
Name: Capivasertib
CAS#: 1143532-39-1
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
Appearance: white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | Capivasertib, a novel pyrrolopyrimidine-derived compound, inhibits all AKT isoforms with a potency of 10 nM or less. |
| In vitro activity: | mTOR, a 289-kDa serine/threonine protein kinase, belongs to the PIKK family and is activated through the PI3K and AKT signaling pathways via phosphorylation of specific residues; once activated, mTOR mediates transcription, cytoskeleton organization, cell growth and cell survival. To investigate the effect of AZD5363 on the mTOR pathway, the phosphorylation levels of mTOR were analyzed. In contrast to the inhibited phosphorylation of AKT substrates, AZD5363 exhibited reduced activity in the mTOR pathway, as presented in panels of tumor cell lines in vitro. AZD5363 enhanced the phosphorylation of mTOR, however, this was only observed in the Huh-7 cells. This indicated that AZD5363 significantly stimulated mTOR signaling, but that this was dependent on liver cancer cell type (Fig.4 and 5; P<0.01). Reference: Oncol Lett. 2016 Mar; 11(3): 1685–1692. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774473/ |
| In vivo activity: | To further unravel the mechanism of action of AZD5363 in vivo, this study measured Ki67 and cleaved caspase 3 in short-term AZD5363-treated PDXs (patient-derived xenografts). The percentage of Ki67-positive cells in untreated tumors was lower in AZD5363-sensitive models compared to the resistant ones (p=0.005, Fig. 3A). In addition, treatment with AZD5363 resulted in a greater reduction of Ki67 in sensitive PDXs compared to the resistant tumors (p<0.001). This study also noted that AZD5363 did not induce cleaved caspase 3 across AZD5363-sensitive tumors, consistent with previous findings for this dosing schedule (Fig. S4F and (8)). Given that S6K mediates efficient cap-dependent translation of cyclin D1 and that AKT/GSK3β axis regulates cyclin D1 stability, it was posited that treatment with AZD5363 impaired cell cycle progression through the CDK4/6-cyclin D1 restriction point in sensitive models. Therefore, this study quantified cyclin D1 by IHC in PDXs before and after treatment with AZD5363. These experiments revealed that most of AZD5363-resistant PDXs expressed low levels of cyclin D1, compared to AZD5363-sensitive PDXs (Fig. 3B, S4D, 12 out of 16, 75% vs. 2 out of 8, 25%, receiver operating characteristic (ROC) curve cut-off H-score ≤ 13.3, ROC p=0.066), suggesting that, in AZD5363-resistant tumors, cell cycle progression was not dependent on cyclin D1. It was also observed that, although AZD5363 downregulated cyclin D1 in all the models expressing cyclin D1 (Fig. 3B), the reduction in cyclin D1 was more relevant in AZD5363-sensitive models (p<0.001). Altogether, these results suggest that cyclin D1 downregulation and cell cycle blockade is an important mechanism of action of AZD5363 in vivo. Reference: Clin Cancer Res. 2020 Jul 15; 26(14): 3720–3731. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814659/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 42.89 | 100.0 |
The following data is based on the product molecular weight 428.9152 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Zhang Y, Zheng Y, Faheem A, Sun T, Li C, Li Z, Zhao D, Wu C, Liu J. A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG-1 dependent on the liver cancer cell type. Oncol Lett. 2016 Mar;11(3):1685-1692. doi: 10.3892/ol.2016.4111. Epub 2016 Jan 14. PMID: 26998062; PMCID: PMC4774473. 2. Chen C, Zhang Q, Liu S, Lambrechts M, Qu Y, You Z. AZD5363 Inhibits Inflammatory Synergy between Interleukin-17 and Insulin/Insulin-Like Growth Factor 1. Front Oncol. 2014 Dec 1;4:343. doi: 10.3389/fonc.2014.00343. PMID: 25520943; PMCID: PMC4249256. 3. Gris-Oliver A, Palafox M, Monserrat L, Brasó-Maristany F, Òdena A, Sánchez-Guixé M, Ibrahim YH, Villacampa G, Grueso J, Parés M, Guzmán M, Rodríguez O, Bruna A, Hirst CS, Barnicle A, de Bruin EC, Reddy A, Schiavon G, Arribas J, Mills GB, Caldas C, Dienstmann R, Prat A, Nuciforo P, Razavi P, Scaltriti M, Turner NC, Saura C, Davies BR, Oliveira M, Serra V. Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. Clin Cancer Res. 2020 Jul 15;26(14):3720-3731. doi: 10.1158/1078-0432.CCR-19-3324. Epub 2020 Mar 27. PMID: 32220884; PMCID: PMC7814659. 4. De Velasco MA, Kura Y, Yoshikawa K, Nishio K, Davies BR, Uemura H. Efficacy of targeted AKT inhibition in genetically engineered mouse models of PTEN-deficient prostate cancer. Oncotarget. 2016 Mar 29;7(13):15959-76. doi: 10.18632/oncotarget.7557. PMID: 26910118; PMCID: PMC4941290. |
| In vitro protocol: | 1. Zhang Y, Zheng Y, Faheem A, Sun T, Li C, Li Z, Zhao D, Wu C, Liu J. A novel AKT inhibitor, AZD5363, inhibits phosphorylation of AKT downstream molecules, and activates phosphorylation of mTOR and SMG-1 dependent on the liver cancer cell type. Oncol Lett. 2016 Mar;11(3):1685-1692. doi: 10.3892/ol.2016.4111. Epub 2016 Jan 14. PMID: 26998062; PMCID: PMC4774473. 2. Chen C, Zhang Q, Liu S, Lambrechts M, Qu Y, You Z. AZD5363 Inhibits Inflammatory Synergy between Interleukin-17 and Insulin/Insulin-Like Growth Factor 1. Front Oncol. 2014 Dec 1;4:343. doi: 10.3389/fonc.2014.00343. PMID: 25520943; PMCID: PMC4249256. |
| In vivo protocol: | 1. Gris-Oliver A, Palafox M, Monserrat L, Brasó-Maristany F, Òdena A, Sánchez-Guixé M, Ibrahim YH, Villacampa G, Grueso J, Parés M, Guzmán M, Rodríguez O, Bruna A, Hirst CS, Barnicle A, de Bruin EC, Reddy A, Schiavon G, Arribas J, Mills GB, Caldas C, Dienstmann R, Prat A, Nuciforo P, Razavi P, Scaltriti M, Turner NC, Saura C, Davies BR, Oliveira M, Serra V. Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts. Clin Cancer Res. 2020 Jul 15;26(14):3720-3731. doi: 10.1158/1078-0432.CCR-19-3324. Epub 2020 Mar 27. PMID: 32220884; PMCID: PMC7814659. 2. De Velasco MA, Kura Y, Yoshikawa K, Nishio K, Davies BR, Uemura H. Efficacy of targeted AKT inhibition in genetically engineered mouse models of PTEN-deficient prostate cancer. Oncotarget. 2016 Mar 29;7(13):15959-76. doi: 10.18632/oncotarget.7557. PMID: 26910118; PMCID: PMC4941290. |
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.
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 µM. AZD5363 monotherapy inhibited the proliferation of 41/182 solid and hematologic tumor cell lines with a potency of <3 µM. 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 µM 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)
