WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 207170
CAS#: 2621928-55-8
Description: MRTX1133 is a potent and selective KRAS G12D inhibitor. MRTX1133 targets the KRAS G12D protein in both active and inactive states. In preclinical studies, MRTX1133 exhibited a long half-life, an ability to bind the KRAS G12D protein in both active and inactive states, and selective inhibition of KRAS G12D mutant cancer cells. In G12D mutant tumor models, MRTX1133 showed dose-dependent selective inhibition of the KRAS pathway and tumor regression.
MedKoo Cat#: 207170
Name: MRTX1133
CAS#: 2621928-55-8
Chemical Formula: C33H31F3N6O2
Exact Mass: 600.2461
Molecular Weight: 600.6462
Elemental Analysis: C, 65.99; H, 5.20; F, 9.49; N, 13.99; O, 5.33
Related CAS #: 2621928-55-8
Synonym: MRTX1133; MRTX-1133; MRTX 1133;
IUPAC/Chemical Name: 2-Naphthalenol, 4-[4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-[[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoro-
InChi Key: SCLLZBIBSFTLIN-IFMUVJFISA-N
InChi Code: InChI=1S/C33H31F3N6O2/c1-2-23-26(35)7-4-18-10-22(43)11-24(27(18)23)29-28(36)30-25(13-37-29)31(41-15-20-5-6-21(16-41)38-20)40-32(39-30)44-17-33-8-3-9-42(33)14-19(34)12-33/h1,4,7,10-11,13,19-21,38,43H,3,5-6,8-9,12,14-17H2/t19-,20?,21?,33+/m1/s1
SMILES Code: OC1=CC(C2=C(F)C3=NC(OC[C@@]45CCCN4C[C@H](F)C5)=NC(N6CC(N7)CCC7C6)=C3C=N2)=C8C(C#C)=C(F)C=CC8=C1
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: To be determined
Shelf Life: >2 years if stored properly
Drug Formulation: To be determined
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | MRTX1133 inhibits ERK phosphorylation in the AGS cell line with an IC50 ranging 1-10 nM (AsPC-1, Panc 04.03, Panc 02.03, SW1990, GP2D, Suit2, A427, SNU1033, and HPAC cells). In a 2D viability assay, the IC50 of MRTX1133 is 6 nM against AGS cells (KRAS G12D), while demonstrating more than 500-fold selectivity against MKN1, a cell line which is dependent on KRAS for its growth and survival due to the amplification of wild-type KRAS. |
| In vitro activity: | MRTX-1133 also completely inhibited ERK phosphorylation in Mia PaCa-2 and SW620 cells, harboring KRAS G12C or G12V mutations, respectively (Fig. 5B and D). This can be observed clearly when the profiling data is presented for each compound separately and compared using the 4 cell lines (Fig. 6). Fig. 6.E showed that MRTX-1133 can inhibit KRAS G12C and G12V, albeit with a higher IC50 than its main target of KRAS G12D. This demonstrates MRTX-1133 is very selective towards KRAS G12D versus wild type KRAS and indicates that targeting KRAS G12V could be possible. Reference: SLAS Discov. 2022 Jun;27(4):249-257. https://pubmed.ncbi.nlm.nih.gov/35288294/ |
| In vivo activity: | Intraperitoneal (IP) administration of MRTX1133 at 30 mg/kg in CD-1 mice (Figure 12) resulted in sustained plasma exposure exceeding the free-fraction-adjusted pERK IC50 value in the KRASG12D mutant Panc 04.03 cell line for approximately 8 h. Encouraged by this result, this study evaluated the ability to modulate KRAS-dependent ERK phosphorylation in the Panc 04.03 xenograft tumor model at 30 mg/kg BID (IP) and observed 62% and 74% inhibition of pERK signal at 1 and 12 h after the second dose, respectively (Figure 13). An antitumor efficacy study in this model resulted in MRTX1133 dose-dependent antitumor activity with 94% growth inhibition observed at 3 mg/kg BID (IP) and tumor regressions of −62% and −73% observed at 10 and 30 mg/kg BID (IP), respectively (Figure 14). Reference: J Med Chem. 2022 Feb 24;65(4):3123-3133. https://pubmed.ncbi.nlm.nih.gov/34889605/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 50.0 | 83.24 |
The following data is based on the product molecular weight 600.6462 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Swiatnicki M, Engel L, Shrestha R, Alves J, Goueli SA, Zegzouti H. Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay. SLAS Discov. 2022 Jun;27(4):249-257. doi: 10.1016/j.slasd.2022.03.001. Epub 2022 Mar 12. PMID: 35288294. 2. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133. doi: 10.1021/acs.jmedchem.1c01688. Epub 2021 Dec 10. PMID: 34889605. |
| In vitro protocol: | 1. Swiatnicki M, Engel L, Shrestha R, Alves J, Goueli SA, Zegzouti H. Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay. SLAS Discov. 2022 Jun;27(4):249-257. doi: 10.1016/j.slasd.2022.03.001. Epub 2022 Mar 12. PMID: 35288294. 2. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133. doi: 10.1021/acs.jmedchem.1c01688. Epub 2021 Dec 10. PMID: 34889605. |
| In vivo protocol: | 1. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA. Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem. 2022 Feb 24;65(4):3123-3133. doi: 10.1021/acs.jmedchem.1c01688. Epub 2021 Dec 10. PMID: 34889605. |
