Capivasertib
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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.

Chemical Structure

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Capivasertib
CAS# 1143532-39-1
Product data Instruction

Theoretical Analysis

MedKoo Cat#: 205669
Name: Capivasertib
CAS#: 1143532-39-1
Chemical Formula: C21H25ClN6O2
Exact Mass: 428.17
Molecular Weight: 428.915
Elemental Analysis: C, 58.81; H, 5.87; Cl, 8.27; N, 19.59; O, 7.46

Price and Availability

Size Price Availability Quantity
5mg USD 90 Ready to ship
10mg USD 150 Ready to ship
25mg USD 250 Ready to ship
50mg USD 450 Ready to ship
100mg USD 750 Ready to ship
200mg USD 1350 Ready to ship
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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

More Info: 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)      

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/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 42.9 100.00

Preparing Stock Solutions

The following data is based on the product molecular weight 428.92 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.

Recalculate based on batch purity %
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.

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1: Andrikopoulou A, Chatzinikolaou S, Panourgias E, Kaparelou M, Liontos M, Dimopoulos MA, Zagouri F. "The emerging role of capivasertib in breast cancer". Breast. 2022 Jun;63:157-167. doi: 10.1016/j.breast.2022.03.018. Epub 2022 Apr 1. PMID: 35398754; PMCID: PMC9011110.


2: Howell SJ, Casbard A, Carucci M, Ingarfield K, Butler R, Morgan S, Meissner M, Bale C, Bezecny P, Moon S, Twelves C, Venkitaraman R, Waters S, de Bruin EC, Schiavon G, Foxley A, Jones RH. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial. Lancet Oncol. 2022 Jul;23(7):851-864. doi: 10.1016/S1470-2045(22)00284-4. Epub 2022 Jun 4. PMID: 35671774; PMCID: PMC9630162.


3: Schmid P, Abraham J, Chan S, Wheatley D, Brunt AM, Nemsadze G, Baird RD, Park YH, Hall PS, Perren T, Stein RC, Mangel L, Ferrero JM, Phillips M, Conibear J, Cortes J, Foxley A, de Bruin EC, McEwen R, Stetson D, Dougherty B, Sarker SJ, Prendergast A, McLaughlin-Callan M, Burgess M, Lawrence C, Cartwright H, Mousa K, Turner NC. Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial. J Clin Oncol. 2020 Feb 10;38(5):423-433. doi: 10.1200/JCO.19.00368. Epub 2019 Dec 16. PMID: 31841354.


4: Turner NC, Oliveira M, Howell SJ, Dalenc F, Cortes J, Gomez Moreno HL, Hu X, Jhaveri K, Krivorotko P, Loibl S, Morales Murillo S, Okera M, Park YH, Sohn J, Toi M, Tokunaga E, Yousef S, Zhukova L, de Bruin EC, Grinsted L, Schiavon G, Foxley A, Rugo HS; CAPItello-291 Study Group. Capivasertib in Hormone Receptor- Positive Advanced Breast Cancer. N Engl J Med. 2023 Jun 1;388(22):2058-2070. doi: 10.1056/NEJMoa2214131. PMID: 37256976.


5: Jones RH, Casbard A, Carucci M, Cox C, Butler R, Alchami F, Madden TA, Bale C, Bezecny P, Joffe J, Moon S, Twelves C, Venkitaraman R, Waters S, Foxley A, Howell SJ. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 2020 Mar;21(3):345-357. doi: 10.1016/S1470-2045(19)30817-4. Epub 2020 Feb 5. PMID: 32035020; PMCID: PMC7052734.


6: Rehman SU, Rehman SU, Yoo HH. COVID-19 challenges and its therapeutics. Biomed Pharmacother. 2021 Oct;142:112015. doi: 10.1016/j.biopha.2021.112015. Epub 2021 Aug 5. PMID: 34388532; PMCID: PMC8339548.


7: Sidaway P. Capivasertib delays disease progression. Nat Rev Clin Oncol. 2023 Jun 13. doi: 10.1038/s41571-023-00790-x. Epub ahead of print. PMID: 37311901.


8: Westin SN, Labrie M, Litton JK, Blucher A, Fang Y, Vellano CP, Marszalek JR, Feng N, Ma X, Creason A, Fellman B, Yuan Y, Lee S, Kim TB, Liu J, Chelariu-Raicu A, Chen TH, Kabil N, Soliman PT, Frumovitz M, Schmeler KM, Jazaeri A, Lu KH, Murthy R, Meyer LA, Sun CC, Sood AK, Coleman RL, Mills GB. Phase Ib Dose Expansion and Translational Analyses of Olaparib in Combination with Capivasertib in Recurrent Endometrial, Triple-Negative Breast, and Ovarian Cancer. Clin Cancer Res. 2021 Dec 1;27(23):6354-6365. doi: 10.1158/1078-0432.CCR-21-1656. Epub 2021 Sep 13. PMID: 34518313; PMCID: PMC8639651.


9: Uko NE, Güner OF, Matesic DF, Bowen JP. Akt Pathway Inhibitors. Curr Top Med Chem. 2020;20(10):883-900. doi: 10.2174/1568026620666200224101808. PMID: 32091335.


10: Capivasertib Active against AKT1-Mutated Cancers. Cancer Discov. 2019 Jan;9(1):OF7. doi: 10.1158/2159-8290.CD-NB2018-153. Epub 2018 Nov 14. PMID: 30429128.


11: Capivasertib Doubles PFS in Some Breast Cancers. Cancer Discov. 2023 Feb 6;13(2):250. doi: 10.1158/2159-8290.CD-NB2022-0078. PMID: 36508589.


12: Hua H, Zhang H, Chen J, Wang J, Liu J, Jiang Y. Targeting Akt in cancer for precision therapy. J Hematol Oncol. 2021 Aug 21;14(1):128. doi: 10.1186/s13045-021-01137-8. PMID: 34419139; PMCID: PMC8379749.


13: Kalinsky K, Hong F, McCourt CK, Sachdev JC, Mitchell EP, Zwiebel JA, Doyle LA, McShane LM, Li S, Gray RJ, Rubinstein LV, Patton D, Williams PM, Hamilton SR, Conley BA, O'Dwyer PJ, Harris LN, Arteaga CL, Chen AP, Flaherty KT. Effect of Capivasertib in Patients With an AKT1 E17K-Mutated Tumor: NCI-MATCH Subprotocol EAY131-Y Nonrandomized Trial. JAMA Oncol. 2021 Feb 1;7(2):271-278. doi: 10.1001/jamaoncol.2020.6741. Erratum in: JAMA Oncol. 2021 Sep 30;:null. PMID: 33377972; PMCID: PMC7774047.


14: Sun F, Mu C, Kwok HF, Xu J, Wu Y, Liu W, Sabatier JM, Annweiler C, Li X, Cao Z, Xie Y. Capivasertib restricts SARS-CoV-2 cellular entry: a potential clinical application for COVID-19. Int J Biol Sci. 2021 Jun 11;17(9):2348-2355. doi: 10.7150/ijbs.57810. PMID: 34239361; PMCID: PMC8241724.


15: Ludmir EB, McCaw ZR, Kim DH, Tian L, Wei LJ. Fulvestrant plus capivasertib for metastatic breast cancer. Lancet Oncol. 2020 May;21(5):e233. doi: 10.1016/S1470-2045(20)30228-X. PMID: 32359498.


16: Nasrazadani A, Brufsky AM. Capivasertib inhibits a key pathway in metastatic breast cancer. Lancet Oncol. 2020 Mar;21(3):318-319. doi: 10.1016/S1470-2045(19)30857-5. Epub 2020 Feb 5. PMID: 32035019.


17: Dekker TJA. Fulvestrant plus capivasertib for metastatic breast cancer. Lancet Oncol. 2020 May;21(5):e232. doi: 10.1016/S1470-2045(20)30153-4. PMID: 32359497.


18: Smyth LM, Tamura K, Oliveira M, Ciruelos EM, Mayer IA, Sablin MP, Biganzoli L, Ambrose HJ, Ashton J, Barnicle A, Cashell DD, Corcoran C, de Bruin EC, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Pass M, Rowlands V, Schiavon G, Banerji U, Scaltriti M, Taylor BS, Chandarlapaty S, Baselga J, Hyman DM. Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1E17K-Mutant, ER-Positive Metastatic Breast Cancer. Clin Cancer Res. 2020 Aug 1;26(15):3947-3957. doi: 10.1158/1078-0432.CCR-19-3953. Epub 2020 Apr 20. PMID: 32312891; PMCID: PMC7415507.


19: Crabb SJ, Griffiths G, Marwood E, Dunkley D, Downs N, Martin K, Light M, Northey J, Wilding S, Whitehead A, Shaw E, Birtle AJ, Bahl A, Elliott T, Westbury C, Sundar S, Robinson A, Jagdev S, Kumar S, Rooney C, Salinas-Souza C, Stephens C, Khoo V, Jones RJ. Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID). J Clin Oncol. 2021 Jan 20;39(3):190-201. doi: 10.1200/JCO.20.01576. Epub 2020 Dec 16. PMID: 33326257; PMCID: PMC8078455.


20: Jones RH, Casbard A, Carucci M, Foxley A, Howell SJ. Fulvestrant plus capivasertib for metastatic breast cancer - Authors' reply. Lancet Oncol. 2020 May;21(5):e234. doi: 10.1016/S1470-2045(20)30237-0. PMID: 32359499.