MRTX-1257 is a novel, potent, selective, orally bioavailable and covalent / irreversible inhibitor of KRAS G12C with an IC50 of 900 pM for KRAS dependent ERK phosphorylation in H358 cells. With free fraction exposures well above the cellular potency, MRTX1257 showed a 31% bioavailability in mice. 77% of the experiment's PK/PD targets engagement.
Physicochemical Properties
| Molecular Formula | C33H39N7O2 |
| Molecular Weight | 565.708466768265 |
| Exact Mass | 565.72 |
| Elemental Analysis | C, 70.06; H, 6.95; N, 17.33; O, 5.66 |
| CAS # | 2206736-04-9 |
| Related CAS # | MRTX-1257-d6;2639608-44-7 |
| PubChem CID | 134326084 |
| Appearance | Off-white to pink solid powder |
| LogP | 4.5 |
| Hydrogen Bond Donor Count | 0 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 42 |
| Complexity | 1000 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | CC1=C2C(=CC=C1)C=CC=C2N3CCC4=C(C3)N=C(N=C4N5CCN([C@H](C5)CC#N)C(=O)C=C)OC[C@@H]6CCCN6C |
| InChi Key | YRYQLVCTQFBRLD-UIOOFZCWSA-N |
| InChi Code | InChI=1S/C33H39N7O2/c1-4-30(41)40-19-18-39(20-25(40)13-15-34)32-27-14-17-38(29-12-6-10-24-9-5-8-23(2)31(24)29)21-28(27)35-33(36-32)42-22-26-11-7-16-37(26)3/h4-6,8-10,12,25-26H,1,7,11,13-14,16-22H2,2-3H3/t25-,26-/m0/s1 |
| Chemical Name | 2-[(2S)-4-[7-(8-methylnaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoylpiperazin-2-yl]acetonitrile |
| Synonyms | MRTX-1257; MRTX1257; MRTX 1257 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | KRAS G12C; KRAS(G12C) (IC50 = 900 pM) |
| ln Vitro | MRTX1257 demonstrates rapid, irreversible modification of GDP-bound recombinant KRAS G12C and suppresses ERK phosphorylation with an IC50 = 1 nM in the H358 cell line. MRTX1257 is shown to be highly selective for the targeted Cys12 of KRAS G12C compared to other surface-exposed cysteine residues in NCI-H358 cells in proteomics studies intended to assess global protein modification.[2] |
| ln Vivo | MRTX1257 has a 31% bioavailability in mice, exhibits nearly complete KRAS signaling inhibition in tumor tissue, and completely eradicates durable tumor regression in MIA PaCa-2 xenografts.[2] |
| Animal Protocol |
mice 3 mg/kg, 30 mg/kg IV, Oral gavage |
| References |
[1]. MIRATI THERAPLUTICS. [2]. Mol Cancer Res (2020) 18 (5_Supplement): B30. |
Solubility Data
| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~176.8 mM) Ethanol: ~30 mg/mL (~53.0 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (4.42 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.5 mg/mL (4.42 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7677 mL | 8.8385 mL | 17.6769 mL | |
| 5 mM | 0.3535 mL | 1.7677 mL | 3.5354 mL | |
| 10 mM | 0.1768 mL | 0.8838 mL | 1.7677 mL |