MRTX1133 Property

Density 

1.49±0.1 g/cm3(Predicted)

solubility 

DMSO:50.0(Max Conc. mg/mL);83.24(Max Conc. mM)

form 

A solid

pka

8.05±0.40(Predicted)

color 

Yellow to brown

InChIKey

SCLLZBIBSFTLIN-IFMUVJFISA-N

SMILES

C1=C2C(C(C#C)=C(F)C=C2)=C(C2N=CC3=C(N4CC5NC(CC5)C4)N=C(OC[C@]45C[C@@H](F)CN4CCC5)N=C3C=2F)C=C1O

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H315Causes skin irritation

H319Causes serious eye irritation

Precautionary statements

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P321Specific treatment (see … on this label).

P332+P313IF SKIN irritation occurs: Get medical advice/attention.

P337+P313IF eye irritation persists: Get medical advice/attention.

MRTX1133 Chemical Properties,Usage,Production

Uses

MRTX1133 is a potent and selective KRAS G12D inhibitor that targets KRAS G12D protein in both the active and inactive states. In preclinical studies, MRTX1133 exhibited a long half-life, was able to bind to KRAS G12D protein in both active and inactive states, and selectively inhibited KRAS G12D-mutated cancer cells. In G12D mutant tumor models, it showed dose-dependent selective inhibition of the KRAS pathway and tumor regression.

Description

MRTX1133 is a potent KRAS^G12D inhibitor. Treatment by intraperitoneal (IP) administration is effective against tumours in xenograft mice with KRAS^G12D mutations. However, MRTX1133 has low oral bioavailability (only 0.5%), which may be related to gastrointestinal malabsorption. In addition, MRTX1133 has two hydrogen bond donors (HBDs): a phenolic group and a secondary amine moiety. And the secondary amine molecule is considered to be the main cause of malabsorption. Currently, an oral prodrug of MRTX1133 has been developed to effectively treat tumours in xenograft mice with the KRAS^G12D mutation^[1].

Chemical Properties

Solid powder.

Uses

MRTX1133 is primarily used in studies targeting advanced solid tumours with KRASG12D mutations, such as human pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC) and colorectal cancer.

Biological Functions

MRTX1133 is a noncovalent, potent, and selective KRAS G12D inhibitor. It optimally fills the switch II pocket and extends three substituents to favorably interact with the protein, resulting in an estimated KD against KRAS G12D of 0.2 pM. MRTX1133 prevents SOS1-catalyzed nucleotide exchange and/or formation of the KRAS G12D/GTP/RAF1 complex, thereby inhibiting mutant KRAS-dependent signal transduction. This inhibitor selectively inhibits KRAS G12D mutants but not KRAS wild-type tumor cells. MRTX1133 has single-digit nanomolar activity in cellular assays and marked in vivo efficacy in tumor models harboring KRAS G12D mutations.

target

KRas G12D

storage

Dry, dark and at 0-4℃ for short term (days to weeks) or -20℃ for long term (months to years).

References

[1] XIANG JI*, JIASHENG LU*; Discovery of Prodrug of MRTX1133 as an Oral Therapy for Cancers with KRASG12D Mutation[J]. ACS Omega, 2023. DOI:10.1021/acsomega.3c00329.