Drug Information

Drug (ID: DG01555) and It's Reported Resistant Information

• Name: Capivasertib
• Synonyms: AZD5363; capivasertib; 1143532-39-1; AZD-5363; AZD 5363; UNII-WFR23M21IE; (S)-4-AMINO-N-(1-(4-CHLOROPHENYL)-3-HYDROXYPROPYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE; WFR23M21IE; 4-Amino-N-[(1s)-1-(4-Chlorophenyl)-3-Hydroxypropyl]-1-(7h-Pyrrolo[2,3-D]pyrimidin-4-Yl)piperidine-4-Carboxamide; 4-Piperidinecarboxamide, 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-; 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinecarboxamide; C21H25ClN6O2; CHEMBL2325741; cc-638; 4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidine-4-carboxamide; Capivasertib (JAN/USAN); Capivasertib (AZD5363); MLS006011179; SCHEMBL390243; GTPL7709; AZC5363; DTXSID40150710; EX-A285; US10654855, Example 9; BDBM443385; 2241AH; MFCD22628785; NSC764039; NSC782347; NSC799347; s8019; ZINC43204023; AKOS027323693; BCP9000365; CCG-268989; CS-1284; DB12218; NSC-764039; NSC-782347; NSC-799347; NCGC00345795-01; NCGC00345795-04; AC-32685; HY-15431; SMR004702948; BCP0726000111; A1387; SW220158-1; D11371; J-514447; Q27074756; 0XZ; ALTERNATIVE ROUTE 1: (S)-4-AMINO-N-(1-(4-CHLOROPHENYL)-3-HYDROXYPROPYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDINE-4-CARBOXAMIDE
• Indication:
  In total 2 Indication(s)
  Triple negative breast cancer [ICD-11: 2C60-2C6Y]; Phase 3; [1]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]; Phase 1; [1]
• Target: RAC-gamma serine/threonine-protein kinase (AKT3); AKT3_HUMAN; [1]
• Formula: 6
• IsoSMILES: C1CN(CCC1(C(=O)N[C@@H](CCO)C2=CC=C(C=C2)Cl)N)C3=NC=NC4=C3C=CN4
• InChI: 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
• InChIKey: JDUBGYFRJFOXQC-KRWDZBQOSA-N
• PubChem CID: 25227436
• DrugBank ID: DB12218

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Brain cancer [ICD-11: 2A00]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [1]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [2]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Leiomyosarcoma [ICD-11: 2B58]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [3]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Leiomyosarcoma [ICD-11: 2B58.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Parotid gland cancer [ICD-11: 2B67]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [3]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Parotid gland cancer [ICD-11: 2B67.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Gastric cancer [ICD-11: 2B72]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: PI3-kinase alpha (PIK3CA) [4]

• Molecule Alteration: Missense mutation; p.H1047R (c.3140A>G)
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Stomach; N.A.
• In Vivo Model: GC xenograft (PDGCX) mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

Gastrointestinal system cancer [ICD-11: 2C11]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: PI3-kinase alpha (PIK3CA) [4]

• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Sensitive Disease: Gastrointestinal system cancer [ICD-11: 2C11.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Stomach; N.A.
• In Vivo Model: GC xenograft (PDGCX) mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

Key Molecule: PI3-kinase alpha (PIK3CA) [4]

• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Disease: Gastrointestinal system cancer [ICD-11: 2C11.Y]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Stomach; N.A.
• In Vivo Model: GC xenograft (PDGCX) mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay

Lung cancer [ICD-11: 2C25]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [5]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Melanoma [ICD-11: 2C30]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [6]

• Molecule Alteration: Missense mutation; p.H1968Y (c.5902C>T)
• Sensitive Disease: Melanoma [ICD-11: 2C30.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEK 292T cells; Kidney; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Breast cancer [ICD-11: 2C60]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [7]

• Molecule Alteration: Duplication; p.P68_C77 (c.202_231)
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The duplication p.P68_C77 (c.202_231) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target.

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [8]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [3]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [3]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: HER2 negative breast cancer [ICD-11: 2C60.11]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [5]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: ER positive breast cancer [ICD-11: 2C60.6]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [5]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: ER negative breast cancer [ICD-11: 2C60.7]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [9]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Breast adenocarcinoma [ICD-11: 2C60.1]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: MCF10A cells; Breast; Homo sapiens (Human); CVCL_0598
• In Vivo Model: Male nude mouse (nu/nu:Alpk) xenograft model; Mus musculus
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Ovarian cancer [ICD-11: 2C73]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [5]

• Molecule Alteration: Missense mutation; p.Q79K (c.235C>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.Q79K (c.235C>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [8]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole-exome sequencing

Endometrial cancer [ICD-11: 2C76]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [8]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Endometrial adenocarcinoma [ICD-11: 2C76.0]
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [3]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Endometrial adenocarcinoma [ICD-11: 2C76.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Cervical cancer [ICD-11: 2C77]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [5]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Cervical cancer [ICD-11: 2C77.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Granulosa cell tumor [ICD-11: 2F76]

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [5]

• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Disease: Granulosa cell tumor [ICD-11: 2F76.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Breast; N.A.
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

References

• Ref 1: Durable Control of Metastatic AKT1-Mutant WHO Grade 1 Meningothelial Meningioma by the AKT Inhibitor, AZD5363J Natl Cancer Inst. 2017 Mar 1;109(3):1-4. doi: 10.1093/jnci/djw320.
• Ref 2: Safety and tolerability of AZD5363 in Japanese patients with advanced solid tumorsCancer Chemother Pharmacol. 2016 Apr;77(4):787-95. doi: 10.1007/s00280-016-2987-9. Epub 2016 Mar 1.
• Ref 3: Capivasertib Active against AKT1-Mutated CancersCancer Discov. 2019 Jan;9(1):OF7. doi: 10.1158/2159-8290.CD-NB2018-153. Epub 2018 Nov 14.
• Ref 4: 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 TaxotereJ Transl Med. 2013 Oct 2;11:241. doi: 10.1186/1479-5876-11-241.
• Ref 5: AKT Inhibition in Solid Tumors With AKT1 MutationsJ Clin Oncol. 2017 Jul 10;35(20):2251-2259. doi: 10.1200/JCO.2017.73.0143. Epub 2017 May 10.
• Ref 6: Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K-AKT-mTOR Pathway InhibitorsClin Cancer Res. 2016 Feb 15;22(4):1018-27. doi: 10.1158/1078-0432.CCR-15-1110. Epub 2015 Oct 21.
• Ref 7: Accelerating Discovery of Functional Mutant Alleles in CancerCancer Discov. 2018 Feb;8(2):174-183. doi: 10.1158/2159-8290.CD-17-0321. Epub 2017 Dec 15.
• Ref 8: Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic backgroundMol Cancer Ther. 2012 Apr;11(4):873-87. doi: 10.1158/1535-7163.MCT-11-0824-T. Epub 2012 Jan 31.
• Ref 9: Tumors with AKT1E17K Mutations Are Rational Targets for Single Agent or Combination Therapy with AKT InhibitorsMol Cancer Ther. 2015 Nov;14(11):2441-51. doi: 10.1158/1535-7163.MCT-15-0230. Epub 2015 Sep 8.