| Identification | Back Directory | [Name]
MRTX-849 | [CAS]
2326521-71-3 | [Synonyms]
MRTX-849
Adagrasib
MRTX849(Adagrasib)
Adagrasib/MRTX-849
MRTX849;MRTX-849;MRTX 849
2-PIPERAZINEACETONITRILE, 4-[7-(8-CHLORO-1-NAPHTHALENYL)-5,6,7,8-TETRAHYDRO-2-[[(2S)-1-METHYL-2-PYRR
2-((S)-4-(7-(8-chloronaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile
2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile
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)- | [Molecular Formula]
C32H35ClFN7O2 | [MDL Number]
MFCD32263433 | [MOL File]
2326521-71-3.mol | [Molecular Weight]
604.12 |
| Chemical Properties | Back Directory | [Boiling point ]
860.2±75.0 °C(Predicted) | [density ]
1.295±0.06 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
Soluble in DMSO:1.0(Max Conc. mg/mL);1.7(Max Conc. mM) | [form ]
A crystalline solid | [pka]
9.31±0.40(Predicted) | [color ]
White to yellow | [InChIKey]
PEMUGDMSUDYLHU-ZEQRLZLVSA-N | [SMILES]
N1(C(=O)C(F)=C)CCN(C2N=C(OC[C@@H]3CCCN3C)N=C3CN(C4=C5C(C=CC=C5Cl)=CC=C4)CCC3=2)C[C@@H]1CC#N |
| Hazard Information | Back Directory | [Description]
MRTX-849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favourable drug-like properties, modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signalling. MRTX-849 demonstrated pronounced tumour regression in 17 of 26 (65%) KRASG12C-positive cell line- and patient-derived xenograft models from multiple tumour types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas[1].
| [Uses]
MRTX 849 is used as combination therapy for treatment of cancer. | [Brand name]
Krazati | [General Description]
Class: non-kinase;
Treatment: KRAS(G12C) NSCLC;
Other name: MRTX849;
Elimination half-life: 24 h;
Protein binding = 98.3% | [Biological Activity]
To minimize GSH metabolism, the development candidate MRTX-849 employed a 2-fluoroacrylamide warhead, imparting whole blood stability of >50 h t1/2 across species while maintaining tractable cellular potency (IC50 = 5–14 nM). Metabolism studies of MRTX-849 in hepatocytes showed that GSH conjugation of the 2-fluoroacrylamide was reduced compared to previous analogues containing the unsubstituted acrylamide. Favorable in vitro ADME and physical properties of MRTX-849 translated into moderate to high bioavailability of 26–63% across species tested. In a PK/PD experiment dosed at 10, 30, and 100 mg/kg to NCI-H358 tumor-bearing mice, MRTX-849 demonstrated dose-dependent protein modification with nearly maximal effect at the highest doses[2].
| [Mechanism of action]
Adagrasib selectively modified mutant cysteine 12 in GDP-bound G12C and inhibited KRASdependent signaling. | [Clinical Use]
Adagrasib is an irreversible inhibitor of the RAS GTPase family. It is approved by the FDA for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who have been identified by testing as having a KRAS (G12C) mutation. | [target]
Primary target: KRAS(G12C) | [storage]
Store at -20°C | [References]
[1] Jay B. Fell. “Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.” Journal of Medicinal Chemistry 63 13 (2020): 6679–6693.
[2] J. Christensen. “The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients.” Cancer discovery (2019).
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