Divarasib
Based on 6 publication(s) in Google Scholar
Divarasib (GDC-6036) is an orally active, selective KRASG12C inhibitor with an IC50 of <0.01 μM. Divarasib covalently binds Cys12 in GDP-bound KRASG12C, occupies the switch II pocket, blocks GTP binding and SOS-mediated reactivation, and inhibits oncogenic KRAS signaling. Divarasib induces tumor shrinkage and robust tumor growth inhibition in KRASG12C-positive models and cancer cells. Divarasib can be used for the research of non-small cell lung cancer, colorectal adenocarcinoma, pancreatic ductal adenocarcinoma, and other KRASG12C-mutated solid tumors.
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- Pureza: 99.31%
- No. CAS: 2417987-45-0
- Fòrmula: C29H32ClF4N7O2
- Peso molecular:622.06
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Almacenamiento:Powder -20°C, 3 years , 4°C, 2 years ; In solvent -80°C, 6 months , -20°C, 1 month
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Actividad biológica
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Chemical Information
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Solvente y solubilidad
- Pureza y Documentación
- Referencias
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Publications Citing Use of MedChemExpress (MCE) Divarasib
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Cell Proliferation/Viability Assay
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IP
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Cell Proliferation/Viability Assay
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Bio/Physico-chemical Assay
Actividad biológica
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K-Ras(G12C) <0.01 μM (IC50) |
Divarasib (20 μM; overnight at room temperature) covalently binds to purified KRASG12C protein with complete or near-complete alkylation[1].
Divarasib (18 h) potently inhibits SOS-mediated nucleotide exchange on purified KRASG12C protein with an IC50 of 0.0024 nM[2].
Divarasib (18 h) covalently alkylates KRASG12C in 2D-cultured HCC1171 cells with an IC50 of 2.2 nM[2].
Divarasib (18 h) covalently alkylates KRASG12C in 3D-cultured HCC1171 cells with an IC50 of 0.42 nM, reflecting more accurate target engagement potency in 3D culture[2].
Divarasib (7 days) potently inhibits viability across a panel of KRASG12C-positive cell lines with a geometric mean IC50 of 0.56 nM, and exhibits 9200-fold selectivity over non-KRASG12C cell lines[2].
Divarasib (10 nM; 4 h) shows high selective reactivity for KRASG12C cysteine over more than 11,000 other reactive cysteines in HCC1171 cells[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
| Species | Dose | Route | CLplasma | Vss | T1/2 | F |
|---|---|---|---|---|---|---|
| Mice[2] | 1 mg/kg | i.v. | 24 mL/min/kg | 2.0 L/kg | 1.4 h | / |
| Mice[2] | 3 mg/kg | p.o. | / | / | 1.4 h | 17 % |
| Rat[2] | 1 mg/kg | i.v. | 69 mL/min/kg | 5.4 L/kg | 1.4 h | / |
| Rat[2] | 3 mg/kg | p.o. | / | / | 1.4 h | 6 % |
| Dog[2] | 0.5 mg/kg | i.v. | 75 mL/min/kg | 4.5 L/kg | 1.2 h | / |
| Dog[2] | 0.5 mg/kg | p.o. | / | / | 1.2 h | 25 % |
| Cynomolgus Monkey[2] | 0.5 mg/kg | i.v. | 10 mL/min/kg | 1.2 L/kg | 1.4 h | / |
| Cynomolgus Monkey[2] | 0.5 mg/kg | p.o. | / | / | 1.4 h | 5 % |
Divarasib (0.1-50 mg/kg; p.o.; daily; 21 days; 0.5-100 mg/kg; p.o.; single dose) induces dose-dependent tumor regression and MAPK pathway suppression in NCI-H358 xenografts, with an ED50 of 2.0 mg/kg for antitumor activity and 6.6 mg/kg for KRASG12C alkylation[2].
Divarasib (0.7-100 mg/kg; p.o.; daily; 21 days; 5-100 mg/kg; p.o.; single dose) induces dose-dependent tumor stasis and MAPK pathway suppression in NCI-H2122 xenografts, with an ED50 of 6.3 mg/kg for antitumor activity and 9.7 mg/kg for KRASG12C alkylation[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C.B-17 SCID (Inbred) (female, 20−21 weeks old, average weight 24.1 g, subcutaneously implanted with human NSCLC NCI-H2030.X1.1 cells)[1]
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Dosage:10 mg/kg; 25 mg/kg; 100 mg/kg
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Administration:p.o.; daily; 7 days
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Result:Exhibited dose-dependent KRAS G12C target engagement across 2, 8, and 24 h post-last dose.
Achieved over 90% KRAS G12C engagement for the 100 mg/kg dose.
Correlated KRAS G12C engagement with percent change in tumor volume from day 0 to day 7.
Induced the greatest tumor shrinkage in all animals at the 100 mg/kg dose.
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Animal Model:C.B-17 SCID (Inbred; female)[2]
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Dosage:0.1-50 mg/kg (daily dosing for antitumor activity); 0.5-100 mg/kg (single dose for PK/PD)
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Administration:p.o.; daily; 21 days; p.o.; single dose
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Result:Drove tumor regression at doses of 5 mg/kg, 15 mg/kg, and 50 mg/kg.
Achieved tumor stasis at 5 mg/kg, while higher doses reduced tumors below the lower limit of detection.
Reached an ED50 of 2.0 mg/kg and ED90 of 13 mg/kg for tumor response.
Achieved ~95% suppression of MAPK target genes DUSP6 and SPRY4 with a single 10 mg/kg dose.
Achieved ~75% KRAS G12C alkylation and 0.2 nM free drug concentration in plasma with a single 10 mg/kg dose.
Reached an alkylation ED50 of 6.6 mg/kg.
| NCT Number | Sponsor | Condition | Start Date |
Phase
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|---|---|---|---|---|
| NCT01329991 | Plexxikon| | 2011-05 | PHASE1 |
Chemical Information
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No. CAS 2417987-45-0
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Appearance Solid
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Peso molecular 622.06
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Fòrmula C29H32ClF4N7O2
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Color White to light yellow
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SMILES
NC1=N[C@]([C@]2=C(C=C3C(N=C(N=C3N4[C@H](CN(CC4)C(C=C)=O)C)OC[C@H]5N(CCC5)C)=C2F)Cl)=C(C(C)=C1)C(F)(F)F
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Synonyms
GDC-6036
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Publications (6)
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Journal Impact Factor
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Most Recent
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Ann Oncol
Genomic landscape of clinically acquired resistance alterations in patients treated with KRASG12C inhibitors. [Abstract]2025 Jun;36(6):682-692. PMID: 39914665
Divarasib purchased from MedChemExpress. Usage Cited in: Ann Oncol. 2025 Jun;36(6):682-692. [Abstract]
Divarasib exhibited a half-maximal inhibitory concentration (IC50) of 0.19 nmol/L in the MIA PaCa‑2 cell line harboring only the single KRASG12C mutation.
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Cell
2024 Oct 31;187(22):6379-6392.e17. PMID: 39255801
Divarasib purchased from MedChemExpress. Usage Cited in: Cell. 2024 Oct 31;187(22):6379-6392.e17. [Abstract]
IP of active GTP-bound Rap1 using GST-RalGDS-RBD of HeLa cells transiently overexpressing EGFP-Rap1A(WT) and EGFP-Rap1A(G12C, L96F) and treated with different concentrations of Divarasib (10-50 μM; 12 h). The results showed that treatment with Divarasib effectively inhibited the activity of Rap1A(G12C, L96F).
Divarasib purchased from MedChemExpress. Usage Cited in: Cell. 2024 Oct 31;187(22):6379-6392.e17. [Abstract]
Relative growth of MOLM-13-KRAS-G12C, MOLM-13-NRAS-G12C, and MOLM-13-KRAS-G12D cells after treatment with K-Ras(G12C) inhibitors (Divarasib et al.) for 72 h.
Divarasib purchased from MedChemExpress. Usage Cited in: Cell. 2024 Oct 31;187(22):6379-6392.e17. [Abstract]
Surface plasmon resonance experiment with Divarasib and RalA(WT), Rap1A(WT), and RhoA(WT). The results showed that Divarasib bound reversely to both RalA(WT) and Rap1A(WT), whereas no binding to RhoA(WT) was detected.
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Cancer Discov
Sotorasib is a pan-RASG12C inhibitor capable of driving clinical response in NRASG12C cancers. [Abstract]2024 May 1;14(5):727-736. PMID: 38236605 -
Nat Cancer
The MEK-RAF molecular glue IK-595 has potent antitumor activity across RAS/MAPK pathway-altered cancers. [Abstract]2026 Jan;7(1):116-130. PMID: 41482524 -
ACS Omega
Application and Cross-Validation of a High-Throughput SPR Method for Characterizing Covalent Binding Ligands. [Abstract]2025 Jul 4;10(27):29637-29646. PMID: 40687013 -
Solvente y solubilidad
DMSO : 100 mg/mL (160.76 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 2.5 mg/mL (4.02 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
Add each solvent one by one: 10% DMSO 90% (20% SBE-β-CD in Saline)
Solubility: ≥ 2.5 mg/mL (4.02 mM); Clear solution
This protocol yields a clear solution of ≥ 2.5 mg/mL (saturation unknown).
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (25.0 mg/mL) to 900 μL 20% SBE-β-CD in Saline, and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C, storage for one week): 2 g SBE-β-CD powder is dissolved in 10 mL Saline, completely dissolve until clear.
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Pureza y Documentación
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Ficha de datos (293 KB)
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SDS (252 KB)
- English - EN (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
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Instrucciones de manejo (2659 KB)
Referencias
[1]. Meng L, et al. Assessment of KRAS G12C Target Engagement by a Covalent Inhibitor in Tumor Biopsies Using an Ultra-Sensitive Immunoaffinity 2D-LC-MS/MS Approach. Anal Chem. 2022 Sep 20;94(37):12927-12933. [Content Brief]
[2]. Endres NF, et al. Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C. J Med Chem. 2026;69(5):5147-5165. [Content Brief]
[3]. Brazel D, et al. Divarasib in the Evolving Landscape of KRAS G12C Inhibitors for NSCLC. Target Oncol. 2024;19(3):297-301. [Content Brief]
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
|---|---|---|---|---|---|
| DMSO | 1 mM | 1.6076 mL | 8.0378 mL | 16.0756 mL | 40.1890 mL |
| 5 mM | 0.3215 mL | 1.6076 mL | 3.2151 mL | 8.0378 mL | |
| 10 mM | 0.1608 mL | 0.8038 mL | 1.6076 mL | 4.0189 mL | |
| 15 mM | 0.1072 mL | 0.5359 mL | 1.0717 mL | 2.6793 mL | |
| 20 mM | 0.0804 mL | 0.4019 mL | 0.8038 mL | 2.0095 mL | |
| 25 mM | 0.0643 mL | 0.3215 mL | 0.6430 mL | 1.6076 mL | |
| 30 mM | 0.0536 mL | 0.2679 mL | 0.5359 mL | 1.3396 mL | |
| 40 mM | 0.0402 mL | 0.2009 mL | 0.4019 mL | 1.0047 mL | |
| 50 mM | 0.0322 mL | 0.1608 mL | 0.3215 mL | 0.8038 mL | |
| 60 mM | 0.0268 mL | 0.1340 mL | 0.2679 mL | 0.6698 mL | |
| 80 mM | 0.0201 mL | 0.1005 mL | 0.2009 mL | 0.5024 mL | |
| 100 mM | 0.0161 mL | 0.0804 mL | 0.1608 mL | 0.4019 mL |
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