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| Targets |
EGFR (WT) 18 nM (IC50) EGFRL858R 0.7 nM (IC50) EGFRL861Q 4 nM (IC50) EGFRL858R/T790M 0.1 nM (IC50) EGFRd746-750 1.4 nM (IC50) EGFRd746-750/T790M 0.89 nM (IC50)
Oritinib targets the epidermal growth factor receptor (EGFR), specifically inhibiting both wild-type and various mutant forms of the EGFR kinase. Its key targets include the L858R, L861Q, L858R/T790M, d746-750, and d746-750/T790M mutants. By binding irreversibly to these mutants, it effectively blocks EGFR-mediated signaling pathways that drive tumor cell proliferation and survival, particularly in the context of acquired resistance to first- and second-generation TKIs. |
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| ln Vitro |
Oritinib (SH-1028) targets the cysteine-797 residue in the ATP binding site by covalent bond formation, forming an irreversible binding to EGFR kinase[1]. In vitro, oritinib (0.001-10 μM) displays strong and selective effects on mutant EGFR cell lines. At lower concentrations or even when the cells are drug-free for at least 6 hours, oritinib (0.1 μM) consistently suppresses the phosphorylation of EGFR in PC-9 and NCI-H1975 cells[1].
In vitro, Oritinib demonstrates potent and selective inhibitory activity against a panel of EGFR kinases. It shows IC50 values of 18 nM, 0.7 nM, 4 nM, 0.1 nM, 1.4 nM, and 0.89 nM against EGFRWT, EGFRL858R, EGFRL861Q, EGFRL858R/T790M, EGFRd746-750, and EGFRd746-750/T790M, respectively. This profile indicates its high potency against common resistance mutations like T790M, while maintaining activity against sensitizing mutations, which is crucial for overcoming acquired resistance in NSCLC. |
| ln Vivo |
In mice xenograft models, oral administration of Oritinib at a daily dose of 5 mg/kg substantially reduces the growth of tumor cells with EGFR sensitive mutation (exon 19 del) and resistant mutation (T790 M) for a consecutive 14 days, without causing TKI-induced weight loss[1]. Oritinib is widely dispersed from the plasma into the tissues and exhibits high bioavailability[1].
In vivo, Oritinib has shown antitumor efficacy in preclinical models of NSCLC. As a third-generation EGFR TKI designed to overcome T790M-mediated resistance, it is expected to effectively inhibit tumor growth in xenograft models harboring EGFR mutations, including the T790M resistance mutation. While specific in vivo data is limited, its mechanism of action and potency suggest significant antitumor activity in animal models of EGFR-mutant lung cancer. |
| Enzyme Assay |
Cell-free assays for Oritinib typically involve measuring its inhibitory activity against EGFR kinases using biochemical kinase assays. In these assays, the compound's IC50 values are determined by measuring the phosphorylation of a peptide substrate in the presence of varying concentrations of the inhibitor. These assays are crucial for characterizing the compound's potency and selectivity profile against a panel of wild-type and mutant EGFR kinases.
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| Cell Assay |
Cell Proliferation Assay[1]
Cell Types: A431 (EGFRWT ), H3255 (EGFRL858R), PC-9 (EGFRd746-750) and NCI-H1975 (EGFRL858R/T790M) cells Tested Concentrations: 0.001, 0.01, 0.1, 1, and 10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Selectively inhibited EGFR-mutated NCI-H1975, H3255 and PC-9 cells, with IC50s of 3.93±1.12, 9.39±0.88 and 7.63±0.18 nmol/L, respectively, which were about 198-, 83- and 102-fold more sensitive than the inhibition of wild -type EGFR in A431 cells (IC50=778.89±134.74 nM). In vitro cellular assays are conducted to evaluate the functional activity of Oritinib. EGFR-mutant cancer cell lines, such as those harboring L858R/T790M mutations, are treated with the compound. Cell viability, proliferation, and EGFR phosphorylation are measured to assess the inhibition of EGFR signaling and the compound's anti-proliferative effects. These assays confirm that Oritinib effectively inhibits the growth of cells driven by mutant EGFR. |
| Animal Protocol |
Animal/Disease Models: 6-8 weeks old female mice bearing NCI-H1975 and A431 xenograft models[1]
Doses: 2.5, 5 , and 15 mg/kg Route of Administration: Orally administered one time/day for consecutive 14 days Experimental Results: Led to a significant inhibition of tumor cell growth in both PC-9 (exon 19 del) and NCI-H1975 (L858R/T790M) xenograft models. Animal/Disease Models: NCI-H1975 tumor-bearing mice[1] Doses: 2.5, 5, and 15 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: Oral administration for 1 day or 14 days. Experimental Results: The Tmax is 1.5-2 h, indicating rapidly distributed into tissues, including lung tumor tissues. The AUC0–t values in plasma were 118, 300 and 931 ng×h/mL on Day 1, while 272, 308 and 993 ng×h/ml on Day 14, respectively. In vivo animal experiments typically involve xenograft models of NSCLC. Mice bearing tumors with EGFR mutations, including the T790M resistance mutation, are administered Oritinib, often via oral gavage. Tumor growth is monitored over time to assess the compound's efficacy in inhibiting tumor progression. These studies are essential for demonstrating the in vivo antitumor activity of the compound. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of Oritinib are typical of an orally bioavailable small molecule TKI. Its molecular weight is 539.67. The compound is designed to have favorable drug-like properties, including good permeability and metabolic stability, to support oral administration. While detailed PK parameters are not widely published, its development as a therapeutic agent implies a pharmacokinetic profile suitable for once-daily dosing in humans.
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| Toxicity/Toxicokinetics |
The toxicity profile of Oritinib is likely consistent with other EGFR TKIs. Common adverse effects associated with this class of drugs include diarrhea, skin rash, and fatigue. As a third-generation inhibitor, it is designed to have improved selectivity for mutant EGFR over wild-type EGFR, which may lead to a more favorable safety profile with reduced skin and gastrointestinal toxicities compared to earlier-generation TKIs.
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| References | |
| Additional Infomation |
Oritinib is a third-generation EGFR TKI developed to overcome T790M-mediated resistance in NSCLC. Its mechanism of action involves irreversible binding to mutant EGFR, blocking downstream signaling pathways that drive tumor growth. The compound is currently in clinical development for the treatment of EGFR-mutant NSCLC. It represents a promising therapeutic option for patients who have developed resistance to first- and second-generation EGFR inhibitors.
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| Molecular Formula |
C31H37N7O2
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|---|---|
| Molecular Weight |
539.67
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| Exact Mass |
539.3
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| CAS # |
2035089-28-0
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| Related CAS # |
Oritinib mesylate;2180164-79-6
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| PubChem CID |
122666966
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
10
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| Heavy Atom Count |
40
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| Complexity |
843
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1C=CC2N3CCCCC3=C(C3C=CN=C(NC4C=C(C(N(CCN(C)C)C)=CC=4OC)NC(=O)C=C)N=3)C=2C=1
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| InChi Key |
PLUKVDOZEJBBIS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C31H37N7O2/c1-6-29(39)33-23-19-24(28(40-5)20-27(23)37(4)18-17-36(2)3)35-31-32-15-14-22(34-31)30-21-11-7-8-12-25(21)38-16-10-9-13-26(30)38/h6-8,11-12,14-15,19-20H,1,9-10,13,16-18H2,2-5H3,(H,33,39)(H,32,34,35)
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| Chemical Name |
N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
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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: 125 mg/mL (231.62 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8530 mL | 9.2649 mL | 18.5298 mL | |
| 5 mM | 0.3706 mL | 1.8530 mL | 3.7060 mL | |
| 10 mM | 0.1853 mL | 0.9265 mL | 1.8530 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.
Link: https://clinicaltrials.gov/ct2/show/NCT06080776
Conditions:Non-small Cell Lung CancerLink: https://clinicaltrials.gov/ct2/show/NCT04808648
Conditions:Healthy Male VolunteersLink: https://clinicaltrials.gov/ct2/show/NCT04239833
Conditions:Non-Small Cell Lung Cancer
Title:Pharmacokinetic Study of SH-1028 Tablets in Healthy Subjects Under Fasting and Fed Conditions
Status:Unknown status
updateDate:2019-06-04
Ctid:NCT03973632
Link: https://clinicaltrials.gov/ct2/show/NCT03973632
Conditions:Healthy VolunteerLink: https://clinicaltrials.gov/ct2/show/NCT03823807
Conditions:Non-Small Cell Lung CancerLink: https://clinicaltrials.gov/ct2/show/NCT03618043
Conditions:Advanced Solid CancerLink: https://clinicaltrials.gov/ct2/show/NCT03603262
Conditions:Non-small Cell Lung CancerProducts are for research use only; We do not sell to patients
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