| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg | |||
| Other Sizes |
| Targets |
The target is Pan-KRas (multiple mutant isoforms of the KRas protein). KRas is a small GTPase that cycles between an active GTP-bound and an inactive GDP-bound state to regulate cell growth and survival. Pan KRas-IN-1 effectively targets a broad spectrum of KRas mutations, suppressing the phosphorylation of the downstream effector ERK across various cancer cell lines.
|
|---|---|
| ln Vitro |
For several KRas isoforms (such as G12D, G12V, G12R, G12A, G12S, G13D, Q61H, and WT), Pan KRas-IN-1 (Example 5) has a strong binding ability to KRas, with an IC50 of less than 2 nM [1]. In various cells, including AsPC-1 (G12D, IC50 = 9 nM), A549 (G12S, IC50 = 11 nM), HCT116 (G13D, IC50 = 23 nM), NCI-H358 (G12C, IC50 = 6 nM), NCI-H460 (Q61H, IC50 = 12 nM), NCI-H727 (G12V, IC50 = 29 nM), MKN1 (WT, IC50 = 32 nM), and PSN-1 (G12R, IC50 = 681 nM) [1]. With IC50 values of 32 nM (G12A), 28.1 nM (G12C), 20.25 nM (G12D), 1742 nM (G12R), 94 nM (G12V), 50 nM (G12W), 610 nM (G13D), and 58 nM (Q61H), Pan KRas-IN-1 (0-3000 nM; 5 d) demonstrates antiproliferative effect against Adagrasib (MRTX849) resistance mutations in mouse 3T3 fibroblasts.
The compound exhibits high binding capacity and potent inhibition across a range of KRas mutants. It effectively suppresses the phosphorylation of ERK, a downstream effector, across various cancer cell lines harboring KRas mutations. Potency data indicates it is highly active, with IC50 values as low as 32 nM for some mutants (e.g., for one mutant is 32 nM, for PSN-1 cells with G12R mutation the IC50 is 681 nM). |
| ln Vivo |
Specific in vivo data for Pan KRas-IN-1 are not detailed. However, as a pan-KRas inhibitor, it is intended for in vivo studies in mouse xenograft models of KRas-mutant cancers. Its ability to overcome resistance to G12C inhibitors is a key area of investigation, as the emergence of secondary mutations often limits the efficacy of existing targeted therapies.
|
| Enzyme Assay |
Biochemical assays for Pan KRas-IN-1 typically measure the inhibition of KRas-effector binding. Nucleotide Exchange Assays: Incubate GDP-bound recombinant KRas (various mutants) with the compound, then add SOS and GTP. Measure the GTP-loading using a GTPase-Glo assay. Alternatively, use a fluorescence polarization assay with a labeled effector (e.g., Raf-RBD) and KRas to measure inhibition of the protein-protein interaction.
|
| Cell Assay |
The cellular activity is evaluated in a panel of cancer cell lines with specific KRas mutations (e.g., G12C, G12D, G12V, G13D). Cells are seeded in 96-well plates and treated with varying concentrations of Pan KRas-IN-1 for 3-5 days. Cell proliferation is measured using a CellTiter-Glo luminescent assay. Inhibition of the MAPK signaling pathway is confirmed by Western blot for phosphorylated ERK (p-ERK) and total ERK after 2-6 hours of compound treatment.
|
| Animal Protocol |
No detailed in vivo protocols are available. A typical study would use a mouse xenograft model of pancreatic cancer (e.g., PANC-1 harboring G12D mutation) or lung cancer (e.g., NCI-H358 with G12C mutation). Mice bearing established tumors (~150 mm3) would be randomized to receive Pan KRas-IN-1 (e.g., via oral gavage daily) or vehicle control. Tumor volume is measured twice weekly, and p-ERK levels in tumor lysates are assessed to confirm target engagement.
|
| ADME/Pharmacokinetics |
Specific quantitative pharmacokinetic parameters for Pan KRas-IN-1 are not provided in the available literature. As an inhibitor targeting intracellular proteins, its ability to penetrate cell membranes and achieve sufficient intracellular concentrations is a critical aspect of its design. Oral bioavailability is a key design goal for such inhibitors.
|
| Toxicity/Toxicokinetics |
Specific toxicological data for Pan KRas-IN-1 are not detailed. As a potent inhibitor of a protein essential for normal cell function, on-target toxicities are a major concern for pan-KRas inhibitors. The therapeutic window would be determined by the differential dependency of cancer cells on mutant KRas versus normal cells on wild-type KRas signaling.
|
| References | |
| Additional Infomation |
Pan-KRas inhibitors represent a major frontier in cancer drug discovery due to the prevalence of KRas mutations in human cancers (e.g., ~90% of pancreatic, ~50% of colorectal cancers). As of the latest updates, Pan KRas-IN-1 is an experimental pre-clinical research chemical and has not yet undergone clinical trials or received regulatory approval.
|
| Molecular Formula |
C33H36F3N5O3
|
|---|---|
| Molecular Weight |
607.67
|
| Exact Mass |
607.277
|
| CAS # |
2791263-84-6
|
| PubChem CID |
164535036
|
| Appearance |
Off-white to light yellow solid powder
|
| LogP |
5.8
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
11
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
44
|
| Complexity |
1020
|
| Defined Atom Stereocenter Count |
3
|
| SMILES |
C([C@@]12CCCN1C[C@@H](C2)F)OC1=NC2C(=C(C3=CC(=CC4C=CC(=C(C3=4)CC)F)O)N=CC=2C(N2CCC[C@](C2)(O)C)=N1)F
|
| InChi Key |
RZYWNBKMTZABBP-PAXFXPPDSA-N
|
| InChi Code |
InChI=1S/C33H36F3N5O3/c1-3-22-25(35)7-6-19-12-21(42)13-23(26(19)22)28-27(36)29-24(15-37-28)30(40-10-4-8-32(2,43)17-40)39-31(38-29)44-18-33-9-5-11-41(33)16-20(34)14-33/h6-7,12-13,15,20,42-43H,3-5,8-11,14,16-18H2,1-2H3/t20-,32-,33+/m1/s1
|
| Chemical Name |
(3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-3-methylpiperidin-3-ol
|
| 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 and light. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~164.56 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6456 mL | 8.2282 mL | 16.4563 mL | |
| 5 mM | 0.3291 mL | 1.6456 mL | 3.2913 mL | |
| 10 mM | 0.1646 mL | 0.8228 mL | 1.6456 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
