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Anlotinib Dihydrochloride (formerlyknown as AL3818 Dihydrochloride) is a novel and potent multi-kinase inhibitor that inhibits VEGFR2/3,FGFR1-4,PDGFRα/β,c-Kit, and Ret. Anlotinib is a potential antineoplastic and anti-angiogenic receptor tyrosine kinase (RTK) inhibitor. Anlotinib dramatically lowers the number of AN3CA cells in vitro, which are identified by high levels of mutated FGFR2 protein expression. After a 29-day treatment cycle, daily oral administration of anlotinib (5 mg/kg) resulted in a complete response in 55% of treated animals and in a reduced tumor volume and tumor weights of AN3CA tumors by 94% and 96%, respectively. While paclitaxel and carboplatin were unable to stop the growth of the tumor, their combination with anlotinib did not appear to have a better result than Anlotinib treatment alone.
| Targets |
VEGFR2 (IC50 = 0.2 nM); VEGFR3 (IC50 = 0.7 nM); c-Kit (IC50 = 14.8 nM); c-Kit (IC50 = 14.8 nM); c-Kit (IC50 = 14.8 nM)
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| ln Vitro |
Anlotinib shows high selectivity and inhibitory potency (IC 50 <1 nmol/L) for VEGFR2 in comparison to other tyrosine kinases, and it occupies the ATP-binding pocket of the VEGFR2 tyrosine kinase. With IC50 values of 0.2 and 0.7 nmol/L, respectively, anlotinib inhibits VEGFR2 and VEGFR3. With an IC50 value of 26.9 nmol/L, anlotinib has a lower inhibitory potency against VEGFR1. Anlotinib's IC50 values for inhibiting PDGFR-related kinases c-Kit and PDGFRβ are 14.8 and 115.0 nmol/L, in that order. Anlotinib has minimal impact, even at 2000 nmol/L, on the activity of other kinases such as c-Met, c-Src, EGFR, and HER2. In HUVEC, anlotinib has picomolar IC50 values that suppress VEGF-induced signaling and cell proliferation. Nevertheless, in vitro tumor cell proliferation must be directly inhibited by anlotinib at micromolar concentrations. Anlotinib strongly inhibits the migration and formation of tubes in HUVECs as well as the microvessel growth from rat aortic explants in vitro[1].
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| ln Vivo |
Anlotinib decreases vascular density in tumor tissue in vivo. Anlotinib, taken once daily orally, exhibits greater and more comprehensive antitumor efficacy in vivo when compared to the well-known tyrosine kinase inhibitor sunitinib. In certain models, it also leads to tumor regression in nude mice. In mice, it is well tolerated. Some TKIs require doses of 20–100 mg/kg to significantly inhibit tumor growth in mice, but anlotinib is effective at 1.5–1.6 mg/kg daily, which is significantly lower than those doses[1]. Anlotinib has demonstrated extensive activity in vivo against human tumor xenograft models of the non-small cell lung (Calu-3) and glioma (U87MG), liver (SMMC-7721), kidney (Caki-1), colon (SW-620), ovarian (SK-OV-3), and renal (Ana-1). When given orally to Sprague-Dawley rats and beagle dogs, anlotinib is quickly absorbed from the gastrointestinal tract. Oral bioavailability in rats ranges from 23–45%, while in dogs it ranges from 47–74%. Across both species, anlotinib has a wide distribution. When compared to plasma, anlotinib exposure levels in primary tissues like the lung, kidneys, liver, and heart are significantly higher in rats. The brain exposure level and the matching plasma level are similar. Anlotinib concentrates 2.4–2.6 times more in tumor tissue than in plasma in mice with tumors. Anlotinib has a relatively long t1/2 (96 ± 17 h) in humans that doesn't seem to depend on dosage[2]. Anlotinib's terminal half-life in dogs is 22.8±11.0 h, whereas in rats it is 5.1±1.6 h. The primary reason for this discrepancy seems to be the variation in total plasma clearance between the two species (dogs: 0.40±0.06 L/h/kg versus rats: 5.35±1.31 L/h/kg). Rather than α1-acid glycoprotein or γ-globulins, anlotinib is primarily bound to albumin and lipoproteins in human plasma[3].
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| Enzyme Assay |
The use of ELISA allowed for the determination of anlotinib's inhibitory activity against tyrosine kinases. ATP and tyrosine kinase reacted in reaction buffer (50 mmol/L HEPES pH 7.4, 50 mmol/L MgCl2, 0.5 mmol/L MnCl2, 0.2 mmol/L Na3VO4, 1 mmol/L DTT) and were incubated in 96-well plates coated with 20 μg/mL Poly(Glu,Tyr)4:1 for one hour at 37°C. HRP-conjugated anti-mouse IgG was added to the plate after the PY99 antibody had been incubated. Analyzer: A Synergy H4 Hybrid reader was used to measure absorbance at 490 nm following reaction with o-phenylenediamine solution and termination with addition of 2N H2SO4.
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| Cell Assay |
Different test agent concentrations are applied to serum-starved HUVEC, Mo7e, U-87MG, and A431 cells for 1.5 hours. The cells are then stimulated for 10 minutes with VEGF (20 ng/mL), SCF-1 (2.5 ng/mL), PDGF-BB (10 ng/mL), or EGF (10 ng/mL). The designated antibodies are used to probe cell lysates.
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| Animal Protocol |
human colon cancer SW620 xenograft model（Balb/cA-nude mice, 5-6 weeks old)
0.75, 1.5, 3 and 6 mg/kg oral |
| References |
| Molecular Formula |
C23H24CL2FN3O3
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|---|---|
| Molecular Weight |
480.36
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| Exact Mass |
479.1178752
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| Elemental Analysis |
C, 57.51; H, 5.04; Cl, 14.76; F, 3.96; N, 8.75; O, 9.99
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| CAS # |
1360460-82-7
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| Related CAS # |
1058156-90-3;1360460-82-7 (HCl);
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| Appearance |
Solid powder
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| SMILES |
CC1=CC2=C(N1)C=CC(=C2F)OC3=C4C=C(C(=CC4=NC=C3)OCC5(CC5)N)OC.Cl.Cl
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| InChi Key |
UUAKQNIPIXQZFN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H22FN3O3.2ClH/c1-13-9-15-16(27-13)3-4-19(22(15)24)30-18-5-8-26-17-11-21(20(28-2)10-14(17)18)29-12-23(25)6-7-23;;/h3-5,8-11,27H,6-7,12,25H2,1-2H3;2*1H
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| Chemical Name |
1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine;dihydrochloride
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| Synonyms |
AL3818 dihydrochloride; AL-3818 dihydrochloride; AL 3818 dihydrochloride; Anlotinib HCl; AL3818; AL 3818; AL-3818; Anlotinib; Catequentinib
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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:≥ 60 mg/mL
Water: Ethanol: |
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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 | 2.0818 mL | 10.4089 mL | 20.8177 mL | |
| 5 mM | 0.4164 mL | 2.0818 mL | 4.1635 mL | |
| 10 mM | 0.2082 mL | 1.0409 mL | 2.0818 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 |
| NCT05481645 | Recruiting | Drug: TQB2450 injection Drug: Carboplatin Injection |
Advanced Endometrial Cancer Sarcoma of Uterus |
Chia Tai Tianqing Pharmaceutical Group Co., Ltd. |
August 22, 2022 | Phase 2 |
The lung metastasis changes in patients of alveolar soft tissue sarcoma with lung metastasis during treatment.J Hematol Oncol.2016 Oct 4;9(1):105. |
Duration of treatment and tumor size changes of 20 patients who received 12mg QD at the 2/1 schedule. J Hematol Oncol.2016 Oct 4;9(1):105. |
Plasma concentrations of anlotinib over time after a single oral dose of anlotinib capsules at 5 (green line), 10 (purple line), 12 (blue line), or 16mg anlotinib/person (red line) in male (solid circles) and female cancer patients (open circles) (a).bCorrelation of dose with plasma AUC0–120h.cCorrelation of dose with plasmaCmax.dCorrelation of dose witht1/2.ePlasma concentrations of anlotinib (24h after daily dosing) over time during multiple oral doses of anlotinib capsules at 12mg anlotinib/person/day in female cancer patients.fPlasma concentrations of anlotinib (24h after daily dosing) over time during multiple oral doses of anlotinib capsules at 12mg anlotinib/person/day in male cancer patients.J Hematol Oncol.2016 Oct 4;9(1):105. |
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