BI-2852 (BI2852) is a novel and potent KRAS inhibitor that binds with nanomolar affinity to the SI/II pocket of KRAS, which is mechanistically distinct from covalent KRASG12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, BI-2852 blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.
Physicochemical Properties
| Molecular Formula | C31H28N6O2 |
| Molecular Weight | 516.5930 |
| Exact Mass | 516.227 |
| CAS # | 2375482-51-0 |
| Related CAS # | (R)-BI-2852;2375482-49-6 |
| PubChem CID | 138756246 |
| Appearance | Off-white to light yellow solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 906.5±65.0 °C at 760 mmHg |
| Flash Point | 502.0±34.3 °C |
| Vapour Pressure | 0.0±0.3 mmHg at 25°C |
| Index of Refraction | 1.752 |
| LogP | 1.94 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 7 |
| Heavy Atom Count | 39 |
| Complexity | 874 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | CN1C=C(N=C1)CN2C=CC3=C2C=C(C=C3)CNCC4=C(C5=CC=CC=C5N4)[C@@H]6C7=C(C=CC(=C7)O)C(=O)N6 |
| InChi Key | JYEQLXOWWLNVDX-PMERELPUSA-N |
| InChi Code | InChI=1S/C31H28N6O2/c1-36-16-21(33-18-36)17-37-11-10-20-7-6-19(12-28(20)37)14-32-15-27-29(24-4-2-3-5-26(24)34-27)30-25-13-22(38)8-9-23(25)31(39)35-30/h2-13,16,18,30,32,34,38H,14-15,17H2,1H3,(H,35,39)/t30-/m0/s1 |
| Chemical Name | (3S)-5-hydroxy-3-[2-[[[1-[(1-methylimidazol-4-yl)methyl]indol-6-yl]methylamino]methyl]-1H-indol-3-yl]-2,3-dihydroisoindol-1-one |
| 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
| ln Vitro | At EC50 5.8 μM and 6.7 μM soft agar and low serum, BI-2852 (Compound 1) (10 nM-10 μM; 2 hours) demonstrates dosing-promoting pERK modulation and anti-proliferative effects in NCI-H358 cell conditions [1]. |
| References |
[1]. Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci U S A. 2019 Aug 6; 116(32):15823-15829. [2]. Drugging all RAS isoforms with one pocket. FUTURE MEDICINAL CHEMISTRY. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~55 mg/mL (~106.47 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.84 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 (4.84 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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 (4.84 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 | 1.9358 mL | 9.6789 mL | 19.3577 mL | |
| 5 mM | 0.3872 mL | 1.9358 mL | 3.8715 mL | |
| 10 mM | 0.1936 mL | 0.9679 mL | 1.9358 mL |