Anlotinib (AL3818) dihydrochloride

Catalog No.S8726

Anlotinib (AL3818) dihydrochloride Chemical Structure

Molecular Weight(MW): 480.36

Anlotinib (AL3818) is a highly potent and selective VEGFR2 inhibitor with IC50 less than 1 nM. It has broad-spectrum antitumor potential in clinical trials.

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Choose Selective VEGFR Inhibitors

Biological Activity

Description Anlotinib (AL3818) is a highly potent and selective VEGFR2 inhibitor with IC50 less than 1 nM. It has broad-spectrum antitumor potential in clinical trials.
Targets
VEGFR2 [1]
(Cell-free assay)
VEGFR3 [1]
(Cell-free assay)
c-Kit [1]
(Cell-free assay)
c-Kit [1]
(Cell-free assay)
c-Kit [1]
(Cell-free assay)
0.2 nM 0.7 nM 14.8 nM 14.8 nM 14.8 nM
In vitro

Anlotinib occupies the ATP-binding pocket of VEGFR2 tyrosine kinase and shows high selectivity and inhibitory potency (IC 50 <1 nmol/L) for VEGFR2 relative to other tyrosine kinases. Anlotinib inhibits VEGFR2 and VEGFR3 with IC50 values of 0.2 and 0.7 nmol/L, respectively. The inhibitory potency of anlotinib against VEGFR1 is lower, with an IC50 value of 26.9 nmol/L. The IC50 values of anlotinib for inhibition of the PDGFR-related kinases c-Kit and PDGFRβ are 14.8 and 115.0 nmol/L, respectively. Anlotinib has little effect on the activity of other kinases, including c-Met, c-Src, EGFR and HER2, even at a concentration of 2000 nmol/L. Anlotinib inhibits VEGF-induced signaling and cell proliferation in HUVEC with picomolar IC50 values. However, micromolar concentrations of anlotinib are required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibits HUVEC migration and tube formation; it also inhibits microvessel growth from explants of rat aorta in vitro[1].

Cell Data
Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID
NCI-H1975 NXuyWVhyS2WubDD2bYFjcWyrdImgZZN{[Xl? M3T4S|jjiIoQvHevcYw> NUT0elNNOjUkgJno MWnD[YxtKH[rYXLpcIl1gSC5YYOg[IVkemWjc3XkJJJmdWG{a3HicJk> NVnlTolPOzB6N{G1NlY>
Calu-1 NYTxSnJGS2WubDD2bYFjcWyrdImgZZN{[Xl? NXrodFZROjRuIES4JIFv\CB5MvMAjYg> MnXJTWM2OD14MT6yN{DPxE4xvJj0QVI1KGkxvJm7JGlEPTB;M{[uPEDPxE4xvJj0QVQ5KGkxvJm7JGlEPTB;MkiuOlQh|ryP78{IeF0zQC54NDFOwG3wxIl? M4XWfVMxPzV3MkSy
A549 M3X3RmNmdGxidnnhZoltcXS7IHHzd4F6 NULrclRwOjRuIES4JIFv\CB5MvMAjYg> Mnz6TWM2OD14ND64NkDPxE4xvJj0QVI1KGkxvJm7JGlEPTB;M{CuN|Qh|ryP78{IeF01QCCq78{JP{BKSzVyPUG3MlI6KM7:Tf-8jJQ:OjhwNkSg{txO97zL MVizNFc2PTJ2Mh?=
HUVEC MWLGeY5kfGmxbjDhd5NigQ>? NYPPcJdSOC5yMTygNE4yNCBzLDCxNEBidmRiMUCwJO69VQ>? NGnUZ5QyNjViaB?= M{nBeYFvdG:2aX7pZkBqdmirYnn0[YQhXkWJRvMAlJN1cW23bHH0[YQhcW62cnHj[YxtfWyjcjDwbI9{eGixconsZZRqd25ib3[gWmVITlJ{IHnuJIEh[2:wY3XueJJifGmxbvMAlIRmeGWwZHXueEB4[XliaX6gTHVXTUNid3n0bEBiKHO3Yn7hco9ud2yjcjDJR|UxKH[jbIXl MVyyPVQ1Pjh3Mx?=
Mo7e MYnGeY5kfGmxbjDhd5NigQ>? MnvPNE4xOSxiMD6xMEAyNCBzMDDhcoQhOTByIN88US=> NWW2cIRjOS53IHi= MoHFRY5td3SrbnniJIlvcGmkaYTl[EBUS0ckgKCx5qCRe3SrbYXsZZRm\CCyaH;zdIhwenmuYYTpc44hd2ZiY,MAlGtqfCxiQVvUJIFv\CCHUlugbY4hVW95ZTDj[Yxtew>? Mk\JNlk1PDZ6NUO=
U-87MG NXzSOWFoTnWwY4Tpc44h[XO|YYm= NE\WOWgxNjBzLDCwMlEtKDFuIEGwJIFv\CBzMECg{txO NYjVPIRLOS53IHi= NHLUOVJqdmirYnn0[YQhWESJRj3CRk1{fGmvdXzheIVlKHCqb4PwbI9zgWyjdHnvckBw\iCSRFfGVu6zNCCDS2SgZY5lKEWUSzDpckBWNTh5TVegZ4VtdHN? MmHZNlk1PDZ6NUO=

... Click to View More Cell Line Experimental Data

Assay
Methods Test Index PMID
Western blot
TP53 / Cleaved-caspase 3 / Cleaved PARP ; 

PubMed: 30139768     


BCPAP (C) and 8505C (F) cells were treated with anlotinib (0, 1, 5, 10 and 15 µM) for 36 h. Cell lysates were prepared and subjected to Western blot to detect the expression of TP53, cleaved caspase 3 (CL-caspase 3) and cleaved PARP (CL-PARP).

Beclin-1 / LC3-I / LC3-II ; 

PubMed: 30755242     


Calu-1 and A549 cells were treated with anlotinib 0–20 μM for 24 h or anlotinib 20 μM for 0–24 h, and the expression levels of beclin-1 and LC3-I/II were detected by western blotting.

Akt / p-Akt / mTOR / p-mTOR ; 

PubMed: 30755242     


Expression of Akt, pAkt, mTOR, p-mTOR, and beclin-1 in lung cancer cells after treatment with concentration gradient anlotinib for 24 h was detected by immunoblotting. 

30139768 30755242
Immunofluorescence
LC3-II ; 

PubMed: 30755242     


Calu-1 and A549 cells on the coverslips were treated with anlotinib or RAPA for 48 h. The punctate patterns of LC3-II were observed by confocal microscopy. 

30755242
Growth inhibition assay
Cell viability; 

PubMed: 30755242     


a, Dose-response curves of Calu-1 and A549 cells to anlotinib treatment. Cells were cultured by anlotinib at various concentrations for 24, 48 and 72 h and cell viability was detected by CCK-8 assay. b, Representative images of clone formation assay.

30755242
In vivo Anlotinib decreases vascular density in tumor tissue in vivo. Compared with the well-known tyrosine kinase inhibitor sunitinib, once-daily oral dose of anlotinib shows broader and stronger in vivo antitumor efficacy and, in some models, causes tumor regression in nude mice. It is well-tolerated in mice. Anlotinib is efficacious at doses (1.5‐6 mg/kg daily) that are significantly lower than effective doses of other TKI, which require doses of 20‐100 mg/kg to achieve significant inhibition of tumor growth in mice[1]. In vivo, anlotinib has showed broad activity against human tumor xenograft models of the colon (SW-620), ovarian (SK-OV-3), liver (SMMC-7721), renal (Caki-1), glioma (U87MG), and non-small cell lung (Calu-3) during dosing period. In Sprague-Dawley rats and beagle dogs, anlotinib is rapidly absorbed from the gastrointestinal tracks after oral administration. The oral bioavailability is 23-45 % in rats and 47-74 % in dogs. Anlotinib exhibits large volume of distribution in both species. In rats, primary tissues, such as the lung, kidneys, liver, and heart, exhibit significant higher exposure levels to anlotinib compared with that in plasma. The exposure level in the brain is comparable with the corresponding plasma level. In tumor-bearing mice, anlotinib concentrates 2.4-2.6 times in tumor tissue than in plasma. In human, anlotinib exhibits a quite long t1/2 (96 ± 17 h), which appeared to be dose-independent[2]. The terminal half-life of anlotinib in dogs (22.8±11.0 h) is longer than that in rats (5.1±1.6 h). This difference appeares to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35±1.31 L/h/kg; dogs, 0.40±0.06 L/h/kg). In human plasma, anlotinib is predominantly bound to albumin and lipoproteins, rather than to α1-acid glycoprotein or γ-globulins[3].

Protocol

Kinase Assay:

[1]

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Enzyme-linked immunosorbent assay:

Inhibitory activity of anlotinib against tyrosine kinases was determined using ELISA. Reaction of ATP with tyrosine kinase was initiated 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 incubated for 1 hour at 37°C in 96-well plates precoated with 20 μg/mL Poly(Glu,Tyr)4:1. The plate was incubated with PY99 antibody and then with HRP-conjugated anti-mouse IgG. After reaction with o-phenylenediamine solution and then termination with the addition of 2N H2SO4, absorbance was measured at 490 nm using a Synergy H4 Hybrid reader.
Cell Research:

[1]

+ Expand
  • Cell lines: HUVEC, Mo7e, U-87MG and A431 cells
  • Concentrations: 0-10 μM
  • Incubation Time: 1.5 h
  • Method:

    Serum-starved HUVEC, Mo7e, U-87MG and A431 cells are treated with different concentrations of test agents for 1.5 h and then stimulated with vascular endothelial growth factor (VEGF; 20 ng/mL), stem cell factor-1 (SCF-1; 2.5 ng/mL), platelet-derived growth factor-BB (PDGF-BB; 10 ng/mL), or epidermal growth factor (EGF; 10 ng/mL) for 10 min, respectively. Cell lysates are probed with the indicated antibodies.


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: human colon cancer SW620 xenograft model(Balb/cA-nude mice, 5-6 weeks old)
  • Formulation: physiological saline
  • Dosages: 0.75, 1.5, 3 and 6 mg/kg
  • Administration: oral
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 96 mg/mL (199.85 mM)
Water 96 mg/mL (199.85 mM)
Ethanol Insoluble

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information

Molecular Weight 480.36
Formula

C23H22FN3O3.2HCl

CAS No. 1360460-82-7
Storage powder
in solvent
Synonyms N/A

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID