Details
Stereochemistry | ABSOLUTE |
Molecular Formula | C32H35ClFN7O2 |
Molecular Weight | 604.117 |
Optical Activity | UNSPECIFIED |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1CCC[C@H]1COC2=NC3=C(CCN(C3)C4=C5C(Cl)=CC=CC5=CC=C4)C(=N2)N6CCN([C@@H](CC#N)C6)C(=O)C(F)=C
InChI
InChIKey=PEMUGDMSUDYLHU-ZEQRLZLVSA-N
InChI=1S/C32H35ClFN7O2/c1-21(34)31(42)41-17-16-40(18-23(41)11-13-35)30-25-12-15-39(28-10-4-7-22-6-3-9-26(33)29(22)28)19-27(25)36-32(37-30)43-20-24-8-5-14-38(24)2/h3-4,6-7,9-10,23-24H,1,5,8,11-12,14-20H2,2H3/t23-,24-/m0/s1
Molecular Formula | C32H35ClFN7O2 |
Molecular Weight | 604.117 |
Charge | 0 |
Count |
|
Stereochemistry | ABSOLUTE |
Additional Stereochemistry | No |
Defined Stereocenters | 2 / 2 |
E/Z Centers | 0 |
Optical Activity | UNSPECIFIED |
Adagrasib (KRAZATI™) is an orally available, potent, small molecule inhibitor of KRAS G12C mutant isoform being developed by Mirati Therapeutics for the treatment of solid tumours harbouring KRAS G12C oncogenic driver mutation, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Adagrasib is an irreversible inhibitor of KRAS G12C that covalently binds to the mutant cysteine in KRAS G12C and locks the mutant KRAS protein in its inactive state that prevents downstream signaling without affecting wild-type KRAS protein. Adagrasib inhibits tumor cell growth and viability in cells harboring KRAS G12C mutations and results in tumor regression in
KRAS G12C-mutated tumor xenograft models with minimal off-target activity. In December 2022, adagrasib received its first approval in the USA for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic NSCLC (as determined by an FDA approved test) who have received ≥ 1 prior systemic therapy. It was approved under accelerated approval based on objective response rate and duration of response, and its continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s). The drug is under regulatory review for NSCLC in the European Union and is in development for CRC in the US. Clinical studies of adagrasib in solid tumours, including CRC, are underway in several countries.
CNS Activity
Sources: https://ascopost.com/issues/november-25-2020/kras-inhibitor-adagrasib-shows-activity-in-non-small-cell-lung-cancer/
Curator's Comment: In a preclinical model, adagrasib penetrated the brain and cerebrospinal cord and led to tumor regression.
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
Target ID: CHEMBL2189121 |
14.0 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | KRAZATI Approved UseKRAZATI is an inhibitor of the RAS GTPase family indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA approved test, who have received at least one prior systemic therapy. Launch Date2022 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
984 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35167329/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ADAGRASIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
|
3253 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35167329/ |
600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ADAGRASIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
37139 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35167329/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ADAGRASIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
|
31600 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35167329/ |
600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ADAGRASIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
23 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35167329/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ADAGRASIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35167329/ |
600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered: |
ADAGRASIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: FASTED |
|
2% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/35167329/ |
600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
ADAGRASIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
Doses
Dose | Population | Adverse events |
---|---|---|
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Disc. AE: Gastrointestinal disorders, Pyrexia... AEs leading to discontinuation/dose reduction: Gastrointestinal disorders (1 patient) Sources: Pyrexia (1 patient) Pneumonia (1 patient) Encephalitis (1 patient) Lung Infection (1 patient) Sepsis (1 patient) Alanine aminotransferase increase (1 patient) Aspartate aminotransferase increase (1 patient) Ejection fraction decrease (1 patient) Muscle weakness (1 patient) Malignant neoplasm progression (2 patients) Cerebrovascular accident (1 patient) Respiratory disorders (5 patients) Hypotension (1 patient) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Alanine aminotransferase increase | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Aspartate aminotransferase increase | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Cerebrovascular accident | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Ejection fraction decrease | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Encephalitis | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Gastrointestinal disorders | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Hypotension | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Lung Infection | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Muscle weakness | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Pneumonia | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Pyrexia | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Sepsis | 1 patient Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Malignant neoplasm progression | 2 patients Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Respiratory disorders | 5 patients Disc. AE |
600 mg 2 times / day steady, oral Highest studied dose Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: |
unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FASTED Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
Drug as perpetrator
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major | yes (co-administration study) Comment: Multiple doses of Itraconazole (200mg QD) increased Cmax and AUC (200mg SD) by 2.4-fold and 4-fold Page: 14.0 |
|||
minor | ||||
minor | ||||
minor | ||||
minor | ||||
minor | ||||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216340Orig1s000MultidisciplineR.pdf Page: 96.0 |
minor | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216340Orig1s000MultidisciplineR.pdf Page: 96.0 |
minor | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216340Orig1s000MultidisciplineR.pdf Page: 57.0 |
yes | |||
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2023/216340Orig1s000MultidisciplineR.pdf Page: 57.0 |
yes |
Sample Use Guides
In Vitro Use Guide
Sources: https://pubmed.ncbi.nlm.nih.gov/31658955
MRTX849 potently inhibits cell growth in the vast majority of KRASG12C-mutant cancer cell lines with IC50 values ranging between 10 nM and 973 nM in the 2D format and between 0.2 nM and 1042 nM in the 3D format.
Substance Class |
Chemical
Created
by
admin
on
Edited
Tue Apr 01 22:51:43 GMT 2025
by
admin
on
Tue Apr 01 22:51:43 GMT 2025
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Record UNII |
8EOO6HQF8Y
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Record Status |
Validated (UNII)
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Record Version |
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FDA ORPHAN DRUG |
756320
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Adagrasib
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Related Record | Type | Details | ||
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TARGET -> INHIBITOR |
Approved to target KRAS G12C mutations in the second-line setting,
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METABOLIC ENZYME -> SUBSTRATE |
the presence of strong CYP 3A4 inhibition by itraconazole can lead to an AUC increase of 400%.
MAJOR
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TRANSPORTER -> INHIBITOR |
Reverses the multidrug resistance mediated by ABCB1 inhibits efflux.
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Related Record | Type | Details | ||
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ACTIVE MOIETY |
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