 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C30H30F2N6O3 |
| Molecular Weight | 560.6 |
| Exact Mass | 560.23 |
| Elemental Analysis | C, 64.28; H, 5.39; F, 6.78; N, 14.99; O, 8.56 |
| Related CAS # | Sotorasib;2296729-00-3;Sotorasib racemate;2252403-56-6 |
| PubChem CID | 137278711 |
| Appearance | Typically exists as solid at room temperature |
| LogP | 4 |
| Hydrogen Bond Donor Count | 1 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 41 |
| Complexity | 1030 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | C[C@H]1CN(CCN1C2=NC(=O)N(C3=NC(=C(C=C32)F)C4=C(C=CC=C4F)O)C5=C(C=CN=C5C(C)C)C)C(=O)C=C |
| InChi Key | NXQKSXLFSAEQCZ-SFHVURJKSA-N |
| InChi Code | InChI=1S/C30H30F2N6O3/c1-6-23(40)36-12-13-37(18(5)15-36)28-19-14-21(32)26(24-20(31)8-7-9-22(24)39)34-29(19)38(30(41)35-28)27-17(4)10-11-33-25(27)16(2)3/h6-11,14,16,18,39H,1,12-13,15H2,2-5H3/t18-/m0/s1 |
| Chemical Name | 6-fluoro-7-(2-fluoro-6-hydroxyphenyl)-1-(4-methyl-2-propan-2-ylpyridin-3-yl)-4-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]pyrido[2,3-d]pyrimidin-2-one |
| Synonyms | Sotorasib; AMG-510; 2296729-00-3; ...; Kras mutant-targeting AMG 510; ...; Sotorasib isomer; |
| 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 |
| 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 |
Mutant KRAS G12C (irreversibly binds to the switch II pocket, Ki = 11 nM for KRAS G12C-GDP; IC50 = 0.21 μM for inhibiting KRAS G12C-mediated signaling in H358 cells) [6] |
| ln Vitro |
- Sotorasib (AMG-510) potently inhibited proliferation of KRAS G12C-positive cancer cell lines, with IC50 values of 0.01-0.5 μM (e.g., H358 lung adenocarcinoma: 0.03 μM; MIA PaCa-2 pancreatic cancer: 0.12 μM) as measured by CellTiter-Glo assay. It had no significant effect on KRAS wild-type or non-G12C mutant cells (IC50 > 10 μM) [6] - In H358 cells, sotorasib (0.1-1 μM) dose-dependently reduced phosphorylation of KRAS downstream effectors (p-ERK, p-AKT, p-S6) within 2 hours (Western blot), with maximal inhibition at 1 μM [6] - The compound (1 μM) induced apoptosis in KRAS G12C-positive cells (Annexin V/PI staining) and reduced colony formation (by 80% in H358 cells) compared to vehicle [6] |
| ln Vivo |
- In mice bearing H358 xenografts (KRAS G12C), sotorasib (10-180 mg/kg, oral gavage, daily for 21 days) caused dose-dependent tumor regression: 180 mg/kg led to 90% tumor growth inhibition (TGI) and 30% complete regression. No significant effect was observed in KRAS wild-type A549 xenografts [6] - In a patient-derived xenograft (PDX) model of KRAS G12C colorectal cancer, sotorasib (100 mg/kg, oral) reduced tumor volume by 65% after 28 days, with decreased p-ERK levels in tumor tissues (immunohistochemistry) [3] |
| Enzyme Assay |
- KRAS G12C binding assay: Purified KRAS G12C-GDP protein was incubated with sotorasib (0.1-100 nM) and analyzed by surface plasmon resonance (SPR). The compound showed slow dissociation (t1/2 = 10 hours) with a Ki of 11 nM. GTPase activity was measured using a luminescent GTP hydrolysis assay, where sotorasib (1 μM) inhibited KRAS G12C GTPase activity by 85% [6] |
| Cell Assay |
- Proliferation assay: KRAS G12C-positive cells (H358, MIA PaCa-2) were seeded in 96-well plates and treated with sotorasib (0.001-10 μM) for 72 hours. Cell viability was assessed using CellTiter-Glo, and IC50 was calculated via nonlinear regression [6] - Western blot for signaling: H358 cells were serum-starved, treated with sotorasib (0.1-1 μM) for 2 hours, then lysed. Lysates were probed with antibodies against p-ERK, p-AKT, and total ERK/AKT. Band intensities were normalized to β-actin [6] |
| Animal Protocol |
- Xenograft model: Nude mice were subcutaneously injected with H358 cells (5×10⁶). When tumors reached 100-200 mm³, sotorasib (10-180 mg/kg) was administered by oral gavage once daily. Tumor volume (calipers) and body weight were measured twice weekly for 21 days. Tumor tissues were harvested for immunohistochemical analysis of p-ERK [6] - PDX model: Mice bearing KRAS G12C colorectal cancer PDXs received sotorasib (100 mg/kg, oral) daily for 28 days. Tumor growth was monitored, and Ki-67 (proliferation marker) expression was quantified [3] |
| ADME/Pharmacokinetics |
- In mice, oral administration of sotorasib (10 mg/kg) showed 70% bioavailability, with peak plasma concentration (Cmax) of 2.3 μg/mL at 1 hour. It had a plasma half-life (t1/2) of 4.5 hours and good tumor penetration (tumor/plasma ratio = 3.2) [6] - In patients, sotorasib (960 mg, oral) reached Cmax of 7.1 μg/mL at 1.5 hours, with a terminal t1/2 of 5 hours. Plasma protein binding was 95% [4] |
| Toxicity/Toxicokinetics |
- In preclinical studies, sotorasib (up to 300 mg/kg, oral) showed no significant toxicity in mice, with normal liver/kidney function markers [6] - In clinical trials, common adverse events (≥15%) included diarrhea (34%), nausea (25%), and fatigue (21%). Grade 3/4 toxicities were rare (<5%), with no dose-limiting nephrotoxicity or hepatotoxicity [4] |
| References |
[1]. Cancer Res (2019) 79 (13_Supplement): 4484. [2]. Cancer Res (2019) 79 (13_Supplement): 4455. [3]. Cancer Commun (Lond) . 2022 Aug;42(8):716-749. [4]. Cancer Res Commun . 2022 May;2(5):342-352. [5]. Cancer Res (2019) 79 (13_Supplement): 3090. [6]. Nature. 2019 Nov;575(7781):217-223. |
| Additional Infomation |
- Sotorasib (AMG-510) is a first-in-class covalent inhibitor that irreversibly binds to the GDP-bound form of KRAS G12C, locking it in an inactive state [6] - It is indicated for treating KRAS G12C-mutated non-small cell lung cancer (NSCLC) after prior systemic therapy, with FDA approval in 2021 [3][4] |
Solubility Data
| Solubility (In Vitro) | H2O :< 0.1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.25 mg/mL (2.23 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 12.5 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 | 1.7838 mL | 8.9190 mL | 17.8380 mL | |
| 5 mM | 0.3568 mL | 1.7838 mL | 3.5676 mL | |
| 10 mM | 0.1784 mL | 0.8919 mL | 1.7838 mL |