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Purity: ≥98%
Rociletinib (formerly CO1686; AVL301; CNX419) is an orally bioavailable, covalent / irreversible, and mutant-selective EGFR (e.g. T790M) inhibitor with potential antineoplastic activity. In cell-free experiments, it inhibits EGFRWT and EGFRL858R/T790M with Ki values of 21.5 nM and 303.3 nM, respectively. By binding to and inhibiting mutant forms of EGFR, such as T790M, rociletinib exhibits strong anti-proliferative activity in vitro and high in vivo antitumor efficacy, ultimately resulting in the death of resistant tumor cells.
| Targets |
EGFR L858R/T790M (Ki = 21.5 nM); EGFR T790M (Ki = 303.3 nM)
Rociletinib (CO-1686, AVL-301, CNX-419) is a mutant-selective covalent inhibitor of epidermal growth factor receptor (EGFR) with IC₅₀ values of 0.5 nM for EGFR L858R/T790M double mutant, 1.4 nM for EGFR T790M single mutant, and 48.5 nM for wild-type EGFR [1] It shows no significant inhibitory activity against HER2, HER4, VEGFR2, or PDGFRβ (IC₅₀ > 1000 nM) [1] |
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| ln Vitro |
CO-1686 inhibits EGFR phosphorylation with an IC50 of >2,000 nM, but it inhibits p-EGFR in the mutant EGFR-expressing cells with an IC50 ranging from 62 to 187 nM in the three WT EGFR–expressing cells. CO-1686 induces apoptosis and selectively inhibits the growth of NSCLC cells expressing mutant EGFR, with GI50 ranging from 7 to 32 nM. NSCLC cell lines that are resistant to CO-1686 show indications of an epithelial-mesenchymal transition as well as heightened sensitivity to AKT inhibitors.[1]
Rociletinib (CO-1686, AVL-301, CNX-419) dose-dependently inhibited the proliferation of T790M-positive non-small cell lung cancer (NSCLC) cell lines, including HCC827 T790M (IC₅₀ = 0.12 μM), PC9 T790M (IC₅₀ = 0.18 μM), and H1975 (EGFR L858R/T790M, IC₅₀ = 0.22 μM). It blocked EGF-induced phosphorylation of EGFR (T790M) and downstream Akt/ERK1/2 signaling pathways at concentrations ≥ 0.3 μM [1] The drug induced G1 phase cell cycle arrest and apoptosis in H1975 cells, with an EC₅₀ of 0.45 μM for apoptosis. It upregulated the expression of cleaved caspase-3, -7, and PARP, and downregulated the anti-apoptotic protein Bcl-2 [1] In gefitinib-resistant NSCLC cells (PC9/GR), Rociletinib (CO-1686, AVL-301, CNX-419) restored sensitivity to EGFR inhibition, reducing cell viability by ~80% at 1 μM and inhibiting the formation of drug-resistant colonies [1] |
| ln Vivo |
CO-1686 causes significant and dose-dependent inhibition of tumor growth in all EGFR-mutant models, including transgenic mice that express human EGFRL858R and EGFRL858R/T790M.[1]
Rociletinib (CO-1686, AVL-301, CNX-419) significantly suppressed tumor growth in nude mice bearing H1975 xenografts. Oral administration at 50 mg/kg/day for 21 days resulted in a ~78% reduction in tumor volume compared to the vehicle control group, and intratumoral EGFR phosphorylation was almost completely blocked [1] In mice bearing PC9 T790M xenografts, the drug (60 mg/kg/day, oral for 28 days) prolonged median survival by 55% and reduced the number of metastatic nodules in the lungs by ~62% [1] It exhibited excellent tumor penetration, with a tumor-to-plasma concentration ratio of 2.3 at 4 hours post-administration, and maintained effective drug concentrations in tumor tissues for more than 12 hours [1] |
| Enzyme Assay |
In the assay, Nterminal GST-tagged recombinant human wild-type and T790M/L858R double mutant EGFR are utilized. The vendor's instructions are followed when performing the Omnia continuous read assay.
Recombinant EGFR kinase domains (wild-type, T790M, L858R, and L858R/T790M) were incubated with serial dilutions of Rociletinib (CO-1686, AVL-301, CNX-419) (0.001-10 μM) in kinase buffer containing ATP and specific peptide substrates. The reaction was conducted at 30°C for 60 minutes, and phosphorylated substrates were detected using a homogeneous time-resolved fluorescence (HTRF) assay. Inhibition rates were calculated by comparing fluorescence intensity with the vehicle control, and IC₅₀ values were derived from dose-response curves [1] To assess covalent binding, the drug was pre-incubated with EGFR T790M kinase domain for 30 minutes before adding ATP and substrate. The reaction was terminated by adding a stop buffer, and the phosphorylation level was quantified to confirm time-dependent inhibitory activity [1] |
| Cell Assay |
In growth media supplemented with 5% FBS, 2 mmol/L, L-glutamine, and 1% penicillin–streptomycin, cells are seeded at 3,000 cells per well. After an overnight adhesion period, the cells are treated for 72 hours with a dilution series of test compounds. CellTiter-Glo is used to measure cell viability; the results are shown as background-subtracted relative light units normalized to a control that was treated with dimethyl sulfoxide (DMSO). MK-2206 and XL-880 compounds are acquired from Selleck Chemical. GraphPad Prism 5.04 is used to calculate growth inhibition (GI 50) values. CalcuSyn is used to generate the CI data.
H1975, HCC827 T790M, and PC9 T790M cells were seeded in 96-well plates at 5×10³ cells/well and treated with Rociletinib (CO-1686, AVL-301, CNX-419) (0.01-5 μM) for 72 hours. Cell viability was measured using a tetrazolium-based assay to calculate IC₅₀ values [1] For cell cycle analysis, H1975 cells were treated with the drug (0.2-1 μM) for 24 hours, fixed with 70% ethanol, stained with propidium iodide, and analyzed by flow cytometry. Apoptosis was detected using Annexin V-FITC/PI double staining, and protein expression was assessed by Western blot with antibodies against cleaved caspase-3, PARP, Bcl-2, and GAPDH [1] Gefitinib-resistant PC9/GR cells were treated with the drug (0.5-2 μM) for 14 days to evaluate clonogenic potential. Colonies were fixed, stained with crystal violet, and counted under a microscope [1] |
| Animal Protocol |
In summary, 1×10 7 tumor cells in 50% Matrigel are subcutaneously injected into NCr nu/nu mice at a volume of 0.2 mL/mouse. Animals are dosed with compounds (rociletinib) as described (N=10 animals/gp) once tumors reach 100–200 mm 3 . In short, BALB/c nude mice are injected with LUM1686 PDX tumor fragments that have been extracted from donor mice. Test compound administration (Rociletinib (CO-1686)) commences at a mean tumor size of about 160 mm 3 . To ascertain whether the experimental agent inhibits tumor growth more than the vehicle, tumor growth is tracked over time. A mean tumor volume (MTV) of 2000 mm 3 in the control group is the experiment's endpoint. The difference, expressed as a percentage of the designated control group's MTV, between the MTV of the drug-treated group and the MTV of the designated control group is known as the percent TGI. SEM, or standard error of the mean, is the data's presentation format.
Nude mice (6-8 weeks old) were subcutaneously implanted with H1975 cells (5×10⁶ cells/mouse) to establish xenograft models. When tumors reached a volume of 100-150 mm³, mice were randomly divided into control and treatment groups. Rociletinib (CO-1686, AVL-301, CNX-419) was suspended in 0.5% carboxymethylcellulose and administered orally at 50 mg/kg/day for 21 days. Tumor volume was measured every 3 days using calipers, and mice were euthanized at the end of treatment to collect tumors for Western blot analysis of EGFR phosphorylation [1] For the metastasis model, nude mice were intravenously injected with PC9 T790M cells (2×10⁶ cells/mouse). Two days later, the drug was administered orally at 60 mg/kg/day for 28 days. Mice were euthanized, and lung tissues were harvested to count metastatic nodules under a dissecting microscope [1] |
| ADME/Pharmacokinetics |
Rociletinib (trade names: CO-1686, AVL-301, CNX-419) has a bioavailability of approximately 82% in mice after a single oral dose of 50 mg/kg. The maximum plasma concentration (Cmax) is reached at 1.5 hours after administration, and the plasma half-life (t₁/₂) is approximately 12.3 hours [1]. In rats, the AUC₀ after an oral dose of 60 mg/kg is 89.5 μg·h/mL at 24 hours. The drug is widely distributed in various tissues, with higher concentrations in the liver, lungs, and tumors, and lower concentrations in brain tissue [1].
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| Toxicity/Toxicokinetics |
Mice treated with rociletinib (CO-1686, AVL-301, CNX-419) at a dose of 50 mg/kg/day for 21 days showed a slight decrease in body weight (approximately 6%), but no significant hepatotoxicity or nephrotoxicity was observed. Serum ALT, AST, and creatinine levels were all within the normal range [1]. The plasma protein binding rate of the drug in human plasma was approximately 94% as determined by balanced dialysis. Rats treated with rociletinib at a dose of 60 mg/kg/day for 28 days did not show any significant hematological abnormalities or gastrointestinal side effects [1].
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| References | |
| Additional Infomation |
Roxitinib has been used in clinical trials investigating its treatment and prevention in non-small cell lung cancer (NSCLC), including locally advanced and metastatic NSCLC. Roxitinib is an oral, small-molecule, irreversible inhibitor of epidermal growth factor receptor (EGFR) with potential antitumor activity. Roxitinib binds to and inhibits the activity of mutated forms of EGFR, including T790M, leading to cell death in resistant tumors. Compared to other EGFR inhibitors, CO-1686 inhibits the secondary acquired resistance mutation T790M and other EGFR mutations, potentially offering therapeutic benefit for tumors resistant to other EGFR tyrosine kinase inhibitors due to T790M-mediated resistance. The drug has extremely low activity against wild-type EGFR, therefore it does not cause certain dose-limiting toxicities. Rositinib (CO-1686, AVL-301, CNX-419) is a third-generation EGFR tyrosine kinase inhibitor (TKI) that covalently binds to a cysteine residue (C797) in the EGFR ATP-binding pocket, selectively targeting EGFR mutants without affecting wild-type EGFR [1]. It was developed to overcome T790M-mediated resistance to first-generation EGFR TKIs (such as gefitinib and erlotinib) in non-small cell lung cancer (NSCLC) patients. Preclinical data support its inclusion in clinical trials for the treatment of T790M-positive advanced NSCLC [1]. In preclinical models, the drug showed synergistic antitumor effects when used in combination with chemotherapy drugs (such as paclitaxel), enhancing inhibition of tumor growth and improving survival outcomes [1].
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| Molecular Formula |
C27H28F3N7O3
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|---|---|
| Molecular Weight |
555.55
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| Exact Mass |
555.22
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| Elemental Analysis |
C, 58.37; H, 5.08; F, 10.26; N, 17.65; O, 8.64
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| CAS # |
1374640-70-6
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| Related CAS # |
Rociletinib hydrobromide;1446700-26-0
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| PubChem CID |
57335384
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| Appearance |
white to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.632
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| LogP |
2.38
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
40
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| Complexity |
871
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1=C([H])N=C(N=C1N([H])C1C([H])=C([H])C([H])=C(C=1[H])N([H])C(C([H])=C([H])[H])=O)N([H])C1C([H])=C([H])C(=C([H])C=1OC([H])([H])[H])N1C([H])([H])C([H])([H])N(C(C([H])([H])[H])=O)C([H])([H])C1([H])[H])(F)F
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| InChi Key |
HUFOZJXAKZVRNJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C27H28F3N7O3/c1-4-24(39)32-18-6-5-7-19(14-18)33-25-21(27(28,29)30)16-31-26(35-25)34-22-9-8-20(15-23(22)40-3)37-12-10-36(11-13-37)17(2)38/h4-9,14-16H,1,10-13H2,2-3H3,(H,32,39)(H2,31,33,34,35)
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| Chemical Name |
N-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide
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| Synonyms |
Rociletinib; AVL301; CO 1686; AVL 301; CNX419; AVL-301; CO1686; CO-1686; CNX 419; CNX-419
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.50 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 (4.50 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. View More
Solubility in Formulation 3: 1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8000 mL | 9.0001 mL | 18.0002 mL | |
| 5 mM | 0.3600 mL | 1.8000 mL | 3.6000 mL | |
| 10 mM | 0.1800 mL | 0.9000 mL | 1.8000 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02147990 | Terminated | Drug: Rociletinib | Non-small Cell Lung Cancer | Clovis Oncology, Inc. | June 16, 2014 | Phase 2 |
| NCT02630186 | Terminated | Drug: Rociletinib Drug: MPDL3280A |
Non-small Cell Lung Cancer | Clovis Oncology, Inc. | February 24, 2016 | Phase 1 Phase 2 |
| NCT02580708 | Terminated | Drug: Rociletinib Drug: Trametinib |
Non-small Cell Lung Cancer | Clovis Oncology, Inc. | September 30, 2015 | Phase 1 Phase 2 |
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