| Size | Price | Stock | Qty |
|---|---|---|---|
| 10mg |
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| Other Sizes |
| Targets |
KRAS(G12C) (IC50 = 0.012 μM)
Opnurasib targets the KRAS G12C mutant protein, a constitutively active form of KRAS that drives tumor cell proliferation, survival, and metastasis. KRAS is a small GTPase that cycles between an inactive GDP-bound state and an active GTP-bound state. The G12C mutation (glycine-to-cysteine substitution at codon 12) impairs the intrinsic GTPase activity of KRAS and its interaction with GTPase-activating proteins (GAPs), leading to accumulation of the active GTP-bound form and constitutive activation of downstream signaling pathways, including the RAF-MEK-ERK (MAPK) pathway. Opnurasib covalently binds to the mutant cysteine residue in the switch II region of KRAS G12C, trapping the protein in the inactive GDP-bound conformation. This binding mechanism is distinct from that of sotorasib and adagrasib, which also target KRAS G12C but bind through different chemical interactions. |
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| ln Vitro |
Opnurasib (NVP-JDQ443) inhibits KRAS's GDP-bound inactive conformation[1].
Opnurasib, with IC50 values of 0.018 and 0.063 μM, respectively, promotes the proliferation of the KRASG12C-mutated cell lines NCI-H358 and NCI-H2122, as well as dose-dependent reductions of phosphorylated ERK (pERK) levels[2]. Opnurasib inhibits GDP-bound KRASG12C with low reversible binding affinity to the RAS switch II pocket in a covalent and selective manner. It also prevents the growth of cell lines that are double-mutant for KRAS and KRASG12C, as well as G12C/H95, G12C/R68S, and G12C/Y96[2]. In vitro, opnurasib demonstrates potent and selective inhibition of KRAS G12C mutant-dependent signaling and cell proliferation. The compound inhibits ERK phosphorylation (p-ERK) in KRAS G12C-mutant cancer cell lines (e.g., MIA PaCa-2, NCI-H358) with IC50 values in the low nanomolar range (typically 1-10 nM). In cell proliferation assays, opnurasib inhibits the growth of KRAS G12C-mutant cells with GI50 values of approximately 10-100 nM, while showing minimal activity against KRAS wild-type cells (GI50 >10 μM), indicating excellent selectivity. The compound effectively induces apoptosis in KRAS G12C-mutant cells, as demonstrated by increased caspase-3/7 activity and annexin V staining. In combination with MEK inhibitors (e.g., trametinib) or EGFR inhibitors, opnurasib shows synergistic antiproliferative effects, overcoming resistance mechanisms that limit the efficacy of single-agent therapy. |
| ln Vivo |
Opnurasib (10-100 mg/kg, Orally, daily for 14 days) exhibits antitumor activity in KRAS G12C-mutated CDX models[2].
Opnurasib (Orally, 100 mg/kg, daily (JDQ443) + 7.5 mg/kg, twice daily (TNO155), for 36 days) exhibits higher cell growth inhibition or cell killing than does single-agent JDQ443 when combined with TNO155[2]. In PDX models of colorectal tumors and non-small cell lung cancer, opracitasin produces distinct antitumor responses that are enhanced by concurrent treatment with additional agents[2]. In preclinical xenograft models, opnurasib demonstrates robust in vivo antitumor activity. In mice bearing KRAS G12C-mutant NSCLC xenografts (e.g., NCI-H358 or MIA PaCa-2), oral administration of opnurasib at 30-100 mg/kg twice daily results in significant tumor growth inhibition (TGI >70%) and in some cases tumor regression. The compound shows efficacy in patient-derived xenograft (PDX) models of KRAS G12C-mutant lung and colorectal cancers. In combination with MEK inhibitors or chemotherapy, opnurasib enhances antitumor efficacy and delays the emergence of resistance. In intracranial models of brain metastases, the compound demonstrates brain penetration and antitumor activity, which is clinically relevant given the high incidence of brain metastases in NSCLC patients. In clinical trials, opnurasib has shown promising efficacy in patients with KRAS G12C-mutant NSCLC, with objective response rates (ORR) of approximately 30-40% in Phase 1/2 studies. |
| Enzyme Assay |
The binding affinity and inhibitory activity of opnurasib against KRAS G12C are assessed using biochemical assays. Recombinant KRAS G12C protein (GDP-bound) is incubated with varying concentrations of opnurasib (0.1-1000 nM) in assay buffer. The binding affinity is measured by surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC). The compound's ability to inhibit nucleotide exchange (GDP to GTP) is assessed using a fluorescent nucleotide exchange assay with SOS (son of sevenless) as the exchange factor. The inhibition of RAF binding is measured using a TR-FRET (time-resolved fluorescence resonance energy transfer) assay in which KRAS G12C is incubated with RAF-RBD (RAS-binding domain) in the presence of varying concentrations of opnurasib. IC50 values for nucleotide exchange inhibition and RAF binding inhibition are calculated from dose-response curves.
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| Cell Assay |
Cell Line: Ba/F3 cells
Concentration: 0, 0.3, 1 μM Incubation Time: 30 min, 4 h Result: Inhibited signaling (pERK) and proliferation of the KRAS G12C/H95 double mutants G12C/H95R and G12C/H95Q. Cellular activity of opnurasib is evaluated in KRAS G12C-mutant cancer cell lines including NCI-H358, MIA PaCa-2, and SW1573. Cells are seeded in 96-well plates and treated with opnurasib at concentrations ranging from 0.1 to 10,000 nM for 48-72 hours. Cell viability is assessed by CellTiter-Glo or MTT assays, and GI50 values are calculated. ERK phosphorylation (p-ERK) is measured by Western blot or AlphaLISA after 2-24 hours of treatment. Apoptosis is assessed by caspase-3/7 activity assays and flow cytometry analysis of annexin V/PI staining. Cell cycle distribution is analyzed by propidium iodide staining and flow cytometry. Combination studies with MEK inhibitors (trametinib, cobimetinib) or other agents are performed using the Chou-Talalay method to determine combination indices and assess synergy. |
| Animal Protocol |
KRAS G12C tumor-bearing nude mice (MIA PaCa-2 (PDAC); NCIH2122, LU99, HCC44, NCI-H2030 (NSCLC); and KYSE410 (esophageal cancer))
10, 30, 100 mg/kg Orally, daily for 14 days In preclinical efficacy studies, opnurasib is administered to immunodeficient mice bearing subcutaneous xenografts of KRAS G12C-mutant NSCLC cell lines. Mice are randomized to receive vehicle or opnurasib (10, 30, or 100 mg/kg) via oral gavage once or twice daily for 14-28 days. Tumor volume is measured twice weekly with calipers, and tumor growth inhibition (TGI) is calculated. At study termination, tumors are harvested for analysis of KRAS G12C occupancy (by mass spectrometry), p-ERK levels (by Western blot or immunohistochemistry), and apoptosis markers (cleaved caspase-3). Pharmacodynamic biomarkers are measured in tumor tissue and plasma. In clinical trials (KontRASt-01, NCT04699188; Phase 3 study NCT05132075), patients with KRAS G12C-mutant NSCLC receive opnurasib at 200-400 mg twice daily orally. Efficacy endpoints include objective response rate (RECIST v1.1), progression-free survival (PFS), and overall survival (OS). |
| ADME/Pharmacokinetics |
Pharmacokinetic studies of opnurasib in preclinical species and humans show favorable oral bioavailability and half-life. In rodents, oral bioavailability is approximately 50-80%, with Tmax of 1-3 hours and a terminal half-life of 4-8 hours. In humans, opnurasib is rapidly absorbed after oral administration, with Tmax of 2-4 hours and an effective half-life of approximately 12-15 hours, supporting twice-daily dosing. The compound shows linear pharmacokinetics across the dose range of 100-600 mg. Opnurasib is metabolized primarily by CYP3A4, and its clearance is moderately affected by CYP3A4 inhibitors and inducers. The compound demonstrates good brain penetration in preclinical models, with brain-to-plasma ratios of approximately 0.3-0.5, which is important for activity against brain metastases. In Phase 1 studies, the maximum tolerated dose (MTD) was not reached at doses up to 600 mg twice daily, and the recommended Phase 2 dose was established at 200-400 mg twice daily.
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| Toxicity/Toxicokinetics |
In clinical trials, opnurasib has demonstrated a manageable safety profile. The most common treatment-emergent adverse events include gastrointestinal effects (diarrhea, nausea, vomiting), fatigue, and elevated liver enzymes (ALT, AST). Grade 3 or higher adverse events occur in approximately 10-20% of patients and are manageable with dose modification or supportive care. The compound does not appear to cause the severe hepatotoxicity or interstitial lung disease that has been reported with some other KRAS inhibitors. No dose-limiting toxicities were observed at doses up to 600 mg twice daily in Phase 1 studies. The safety profile of opnurasib compares favorably with that of sotorasib and adagrasib, and the compound is being evaluated in combination with other agents to improve efficacy without significantly increasing toxicity.
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| References | |
| Additional Infomation |
Opnurasib is an inhibitor of the KRAS oncogenic mutation G12C and possesses potential antitumor activity. After administration, opnurasib selectively targets the KRAS G12C mutant and inhibits KRAS G12C mutant-dependent signaling. KRAS is a member of the RAS oncogene family and plays a crucial role in cell signaling, division, and differentiation. KRAS mutations can induce constitutive signal transduction, leading to tumor cell growth, proliferation, invasion, and metastasis.
Drug Indications Treatment of lung cancer (small cell lung cancer and non-small cell lung cancer) Opnurasib (JDQ-443) is a promising next-generation KRAS G12C inhibitor that has advanced to Phase 3 clinical development for the treatment of KRAS G12C-mutant NSCLC. The compound's distinct binding mechanism and favorable safety profile distinguish it from first-generation KRAS G12C inhibitors. Clinical trials are ongoing to evaluate opnurasib as monotherapy in previously treated NSCLC patients (Phase 3, NCT05132075) and in combination with other agents including spartalizumab (anti-PD-1) and ribociclib (CDK4/6 inhibitor) in various solid tumors. The compound is also being investigated for activity against brain metastases, which are common in NSCLC patients. Opnurasib represents a significant advancement in the targeted therapy of KRAS-mutant cancers and has the potential to become a standard-of-care option for patients with KRAS G12C-mutant NSCLC. |
| Molecular Formula |
C29H28CLN7O
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|---|---|
| Exact Mass |
525.2
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| Elemental Analysis |
C, 66.22; H, 5.37; Cl, 6.74; N, 18.64; O, 3.04
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| CAS # |
2653994-08-0
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| Related CAS # |
(S)-JDQ-443;2653994-10-4
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| PubChem CID |
156501355
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| Appearance |
White to off-white solid powder
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| LogP |
4.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
38
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| Complexity |
936
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC2=C(C=NN2)C(=C1Cl)C3=C(N(N=C3C4=CC5=C(C=C4)N(N=C5)C)C6CC7(C6)CN(C7)C(=O)C=C)C
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| InChi Key |
AZUYLZMQTIKGSC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H28ClN7O/c1-5-24(38)36-14-29(15-36)10-20(11-29)37-17(3)25(26-21-13-31-33-22(21)8-16(2)27(26)30)28(34-37)18-6-7-23-19(9-18)12-32-35(23)4/h5-9,12-13,20H,1,10-11,14-15H2,2-4H3,(H,31,33)
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| Chemical Name |
1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one
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| Synonyms |
Opnurasib; 2653994-08-0; NVP-JDQ-443; JDQ-443; JDQ443; JDQ 443; NVP-JDQ443; NVP JDQ443; NVPJDQ443
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~190.1 mM)
Ethanol: ~100 mg/mL (~190.1 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.95 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 20.8 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: ≥ 2.08 mg/mL (3.95 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 20.8 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.) |
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.
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