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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
Structure of ADAGRASIB

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

HIDE SMILES / InChI

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

Curator's Comment: In a preclinical model, adagrasib penetrated the brain and cerebrospinal cord and led to tumor regression.

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
14.0 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
KRAZATI

Approved Use

KRAZATI 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 Date

2022
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
984 ng/mL
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
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

AUC

ValueDoseCo-administeredAnalytePopulation
37139 ng × h/mL
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
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

T1/2

ValueDoseCo-administeredAnalytePopulation
23 h
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

Funbound

ValueDoseCo-administeredAnalytePopulation
2%
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%
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

Doses

DosePopulationAdverse 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)
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)
Sources:
AEs

AEs

AESignificanceDosePopulation
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:
OverviewDrug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
likely
likely
likely
likely
weak (co-administration study)
Comment: 400mg BID increased Rosuvastatin (5mg SD) Cmax and AUC by 1.06-fold and 1.35-fold.
Page: 57.0
likely
weak (co-administration study)
Comment: 600mg SD increased Digoxin (0.25mg SD) Cmax and AUC by 1.05-fold and 1.38-fold.
Page: 57.0
likely
yes (co-administration study)
Comment: 600mg SD increased Warfarin (10mg SD) Cmax and AUC by 1.32-fold and 1.62-fold.
Page: 57 | 98
likely
yes (co-administration study)
Comment: 400mg BID increased Dextromethorphan (30mg SD) Cmax and AUC by 1.90-fold and 1.73-fold.
Page: 57 | 99
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
major
minor
minor
minor
minor
minor
minor
minor
yes
yes
PubMed

PubMed

TitleDatePubMed
Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation.
2022 Jul 14
Patents

Sample Use Guides

Recommended dosage: 600 mg orally twice daily.
Route of Administration: Oral
In Vitro Use Guide
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 Tue Apr 01 22:51:43 GMT 2025
Edited
by admin
on Tue Apr 01 22:51:43 GMT 2025
Record UNII
8EOO6HQF8Y
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
ADAGRASIB
USAN   INN  
Official Name English
KRAZATI
Preferred Name English
2-PIPERAZINEACETONITRILE, 4-(7-(8-CHLORO-1-NAPHTHALENYL)-5,6,7,8-TETRAHYDRO-2-(((2S)-1-METHYL-2-PYRROLIDINYL)METHOXY)PYRIDO(3,4-D)PYRIMIDIN-4-YL)-1-(2-FLUORO-1-OXO-2-PROPEN-1-YL)-, (2S)-
Systematic Name English
MRTX-849
Code English
adagrasib [INN]
Common Name English
KRAS G12C INHIBITOR MRTX849
Common Name English
ADAGRASIB [USAN]
Common Name English
Adagrasib [WHO-DD]
Common Name English
((2S)-4-(7-(8-CHLORONAPHTHALEN-1-YL)-2-(((2S)-1- METHYLPYRROLIDIN-2-YL)METHOXY)-5,6,7,8- TETRAHYDROPYRIDO(3,4-D)PYRIMIDIN-4-YL)-1-(2-FLUOROPROP2-ENOYL)PIPERAZIN-2-YL)ACETONITRILE
Systematic Name English
MRTX849
Code English
Classification Tree Code System Code
FDA ORPHAN DRUG 756320
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
Code System Code Type Description
FDA UNII
8EOO6HQF8Y
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
USAN
KL-25
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
DRUG BANK
DB15568
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
PUBCHEM
138611145
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
WIKIPEDIA
Adagrasib
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
NCI_THESAURUS
C157493
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY NCIT
CAS
2326521-71-3
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
INN
11519
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY INN
DAILYMED
8EOO6HQF8Y
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
EPA CompTox
DTXSID801336759
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
SMS_ID
300000026691
Created by admin on Tue Apr 01 22:51:43 GMT 2025 , Edited by admin on Tue Apr 01 22:51:43 GMT 2025
PRIMARY
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MAJOR
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