Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C26H23N7O2 |
Molecular Weight | 465.5065 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CC#CC(=O)N1CCC[C@H]1C2=NC(=C3N2C=CN=C3N)C4=CC=C(C=C4)C(=O)NC5=CC=CC=N5
InChI
InChIKey=WDENQIQQYWYTPO-IBGZPJMESA-N
InChI=1S/C26H23N7O2/c1-2-6-21(34)32-15-5-7-19(32)25-31-22(23-24(27)29-14-16-33(23)25)17-9-11-18(12-10-17)26(35)30-20-8-3-4-13-28-20/h3-4,8-14,16,19H,5,7,15H2,1H3,(H2,27,29)(H,28,30,35)/t19-/m0/s1
Molecular Formula | C26H23N7O2 |
Molecular Weight | 465.5065 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 1 / 1 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
DescriptionSources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26957112
Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26957112
Acalabrutinib, also known as ACP-196, is a novel irreversible second-generation Bruton’s tyrosine kinase (BTK) inhibitor, which prevents the activation of the B-cell antigen receptor (BCR) signaling pathway and that, was rationally designed to be more potent and selective than ibrutinib. This drug in clinical trials phase III for treatment the treatment of relapsed chronic lymphocytic leukemia. Also in combination with others drugs, Acalabrutinib in phase II of clinical trials for the treatment Glioblastoma Multiforme, Mantle Cell Lymphoma, Squamous Cell Carcinoma of the Head and Neck, Rheumatoid Arthritis and some others.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL5251 Sources: https://www.ncbi.nlm.nih.gov/pubmed/?term=26957112 |
3.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | CALQUENCE Approved UseCALQUENCE is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Launch Date2017 |
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Primary | Unknown Approved UseUnknown |
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Palliative | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
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Primary | Unknown Approved UseUnknown |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
827 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29737219 |
200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ACALABRUTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
323 ng/mL |
100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ACALABRUTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1850 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29737219 |
200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ACALABRUTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
1111 ng × h/mL |
100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ACALABRUTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
0.6 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/29737219 |
200 mg 2 times / day steady-state, oral dose: 200 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ACALABRUTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
0.9 h |
100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ACALABRUTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2.5% |
100 mg 2 times / day multiple, oral dose: 100 mg route of administration: Oral experiment type: MULTIPLE co-administered: |
ACALABRUTINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
400 mg 1 times / day steady, oral Highest studied dose Dose: 400 mg, 1 times / day Route: oral Route: steady Dose: 400 mg, 1 times / day Sources: |
unhealthy, 62 years (range: 44–84 years) Health Status: unhealthy Condition: Relapsed Chronic Lymphocytic Leukemia Age Group: 62 years (range: 44–84 years) Sex: M+F Sources: |
|
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Disc. AE: Neoplasms malignant site unspecified NEC, Aortic stenosis... AEs leading to discontinuation/dose reduction: Neoplasms malignant site unspecified NEC (0.2%) Sources: Page: p. 132Aortic stenosis (0.2%) Dyspnea (0.2%) Leukostasis (0.2%) Thrombocytopenia (0.5%) Pulmonary fibrosis (0.2%) Hemorrhagic bullae (0.2%) Chest pain (non-cardiac) (0.2%) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Aortic stenosis | 0.2% Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Chest pain (non-cardiac) | 0.2% Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Dyspnea | 0.2% Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Hemorrhagic bullae | 0.2% Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Leukostasis | 0.2% Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Neoplasms malignant site unspecified NEC | 0.2% Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Pulmonary fibrosis | 0.2% Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Thrombocytopenia | 0.5% Disc. AE |
100 mg 2 times / day steady, oral Recommended Dose: 100 mg, 2 times / day Route: oral Route: steady Dose: 100 mg, 2 times / day Sources: Page: p. 132 |
unhealthy, adult n = 610 Health Status: unhealthy Condition: hematological malignancies Age Group: adult Sex: M+F Population Size: 610 Sources: Page: p. 132 |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Page: 18, 167 |
no [Ki 8.5 uM] | |||
Page: 18.0 |
no | |||
Page: 18.0 |
no | |||
Page: 18.0 |
no | |||
Page: 19.0 |
no | |||
Page: 18.0 |
no | |||
Page: 18.0 |
no | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 72.0 |
unlikely | unlikely Comment: acalabrutinib does not inhibit P-gp transporter at clnically relevant concentrations; [I]1/IC50 < 0.1, [I]2/IC50 < 10 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 72.0 |
||
Page: 18, 167 |
weak [Ki 11.3 uM] | |||
Page: 18.0 |
weak | |||
Page: 18.0 |
weak | |||
Page: 18.0 |
weak | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 72.0 |
weak | likely Comment: Acalabrutinib is a weak BCRP inhibitor at the intestinal level, per calculations according to FDA Draft Guidance on DDI ([I]1/IC50 < 0.1, [I]2/IC50 = 21); acalabrutinib may increase exposure of BCRP substrates; acalabrutinib may increase methotrexate through inhibition of intestinal BCRP; Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 72.0 |
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Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 82.0 |
yes [Ki 20.6 uM] | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 82.0 |
yes [Ki 23.9 uM] | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 167.0 |
yes [Ki 3.3 uM] | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 82.0 |
yes [Ki 4 uM] | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 167.0 |
yes [Ki 8.5 uM] | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 82.0 |
yes |
Drug as victim
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 37, 72 |
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Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/210259Orig1s000MultidisciplineR.pdf Page: 37.0 |
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26641137
for Chronic Lymphocytic Leukemia: 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion.
Route of Administration:
Oral
In Vitro Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26957112
The differential effects of acalabrutinib on primary chronic lymphocytic leukemia (CLL) cells, T cells, NK cells, and epithelial cells were studied by signaling and functional assays. Acalabrutinib inhibited purified ruton’s tyrosine kinase (BTK) with an IC50 of 3 nM and EC50 of 8 nM in a human whole-blood CD69 B cell activation assay. Acalabrutinib was shown to have improved target specificity over ibrutinib with 323-, 94-, 19-, and 9-fold selectivity over the other TEC kinase family members (ITK, TXK, BMX, and TEC, respectively) and no activity against EGFR.
Substance Class |
Chemical
Created
by
admin
on
Edited
Sat Dec 16 10:01:59 GMT 2023
by
admin
on
Sat Dec 16 10:01:59 GMT 2023
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Record UNII |
I42748ELQW
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Record Status |
Validated (UNII)
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Record Version |
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
477415
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NCI_THESAURUS |
C124801
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NDF-RT |
N0000175605
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NCI_THESAURUS |
C129825
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EU-Orphan Drug |
EU/3/16/1625
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FDA ORPHAN DRUG |
489015
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FDA ORPHAN DRUG |
488915
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I42748ELQW
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DB11703
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C113442
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1420477-60-6
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SUB182073
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m12069
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Acalabrutinib
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DTXSID401026209
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Acalabrutinib
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CHEMBL3707348
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10150
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DE-48
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167707
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Related Record | Type | Details | ||
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ENANTIOMER -> ENANTIOMER |
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SOLVATE->ANHYDROUS | |||
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EXCRETED UNCHANGED |
In the mass balance study, 84% of the dose was received in the feces and 12% of the dose was recovered in the urine, with less than 1% of the dose excreted as unchanged acalabrutinib in urine.
AMOUNT EXCRETED
URINE
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TRANSPORTER -> SUBSTRATE | |||
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TARGET -> INHIBITOR |
Acalabrutinib forms a covalent bond with Cys481 in the BTK adenosine triphosphate (ATP).
IRREVERSIBLE INHIBITOR
IC50
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SALT/SOLVATE -> PARENT |
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METABOLIC ENZYME -> SUBSTRATE |
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OFF TARGET->NON-INHIBITOR |
IC50
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TRANSPORTER -> SUBSTRATE | |||
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SALT/SOLVATE -> PARENT |
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SALT/SOLVATE -> PARENT |
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BINDER->LIGAND |
BINDING
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Related Record | Type | Details | ||
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METABOLITE -> PARENT |
PLASMA; URINE
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT |
PLASMA
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT |
PLASMA; URINE
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT |
FECAL
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METABOLITE -> PARENT |
FECAL
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METABOLITE -> PARENT | |||
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METABOLITE -> PARENT |
PLASMA
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METABOLITE -> PARENT |
Related Record | Type | Details | ||
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IMPURITY -> PARENT |
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Related Record | Type | Details | ||
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ACTIVE MOIETY |
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Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
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SOLUBILITY | CHEMICAL |
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pH CHEMICAL |
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Volume of Distribution | PHARMACOKINETIC |
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SOLUBILITY | CHEMICAL |
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pH CHEMICAL |
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Biological Half-life | PHARMACOKINETIC |
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Tmax | PHARMACOKINETIC |
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ORAL ADMINISTRATION |
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