Anlotinib (AL3818) dihydrochloride

Name: Anlotinib (AL3818) dihydrochloride
Brand: Selleck Chemicals
SKU: S8726
Rating: 5 (4 reviews)

For research use only. Not for use in humans.

Catalog No.S8726

4 publications

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.

Selleck's Anlotinib (AL3818) dihydrochloride has been cited by 4 publications

Purity & Quality Control

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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	Activity Description	PMID
NCI-H1975	MXvD[YxtKH[rYXLpcIl1gSCjc4PhfS=>	M1P0UFjjiIoQvHevcYw>	MknpNlTjiImq	NULPXHRpS2WubDD2bYFjcWyrdImge4F{KGSnY4LlZZNm\CC{ZX3hdoti[my7	NInsdXQ{ODh5MUWyOi=>
Calu-1	NFqySINE\WyuII\pZYJqdGm2eTDhd5NigQ>?		MmfENlQtKDR6IHHu[EA4OuLCiXi=	MnXtTWM2OD14MT6yN{DPxE4xvJj0QVI1KGkxvJm7JGlEPTB;M{[uPEDPxE4xvJj0QVQ5KGkxvJm7JGlEPTB;MkiuOlQh\|ryP78{IeF0zQC54NDFOwG3wxIl?	NX3GTWhzOzB5NUWyOFI>
A549	NHr2OGNE\WyuII\pZYJqdGm2eTDhd5NigQ>?		MkjmNlQtKDR6IHHu[EA4OuLCiXi=	NHzWTmRKSzVyPU[0MlgzKM7:Tf-8jJQ:OjRiaP-8jVshUUN3ME2zNE4{PCEQvF5vwKh1RTR6IHlvwKk8KEmFNUC9NVcvOjlizszN89yJfD1{OD62OEDPxE4xvJm=	NF[3RVM{ODd3NUK0Ni=>
HUVEC	Mle2SpVv[3Srb36gZZN{[Xl?	NFrnO\|YxNjBzLDCwMlEtKDFuIEGwJIFv\CBzMECg{txO	MYexMlUhcA>?	M3j5SoFvdG:2aX7pZkBqdmirYnn0[YQhXkWJRvMAlJN1cW23bHH0[YQhcW62cnHj[YxtfWyjcjDwbI9{eGixconsZZRqd25ib3[gWmVITlJ{IHnuJIEh[2:wY3XueJJifGmxbvMAlIRmeGWwZHXueEB4[XliaX6gTHVXTUNid3n0bEBiKHO3Yn7hco9ud2yjcjDJR\|UxKH[jbIXl	MoXxNlk1PDZ6NUO=
Mo7e	NIfjcHlHfW6ldHnvckBie3OjeR?=	MoLwNE4xOSxiMD6xMEAyNCBzMDDhcoQhOTByIN88US=>	M1r4dFEvPSCq	M4rQNmFvdG:2aX7pZkBqdmirYnn0[YQhW0OI4pEQNgKBmHO2aX31cIF1\WRicHjvd5Bpd3K7bHH0bY9vKG:oIHRihLBMcXRuIFHLWEBidmRiRWLLJIlvKE2xN3WgZ4VtdHN?	MknNNlk1PDZ6NUO=
U-87MG	NVTPbXh1TnWwY4Tpc44h[XO\|YYm=	NH3IT4ExNjBzLDCwMlEtKDFuIEGwJIFv\CBzMECg{txO	NXjjPFNkOS53IHi=	M2WyT4lvcGmkaYTl[EBRTEeILVLCMZN1cW23bHH0[YQheGixc4Doc5J6dGG2aX;uJI9nKFCGR1\S{tItKEGNVDDhcoQhTVKNIHnuJHUuQDePRzDj[Yxtew>?	MmrUNlk1PDZ6NUO=

... Click to View More Cell Line Experimental Data

Assay

Methods	Test Index	PMID
Western blot	TP53 / Cleaved-caspase 3 / Cleaved PARP ; PubMed: 30139768 Endocr Relat Cancer 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 J Exp Clin Cancer Res 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 J Exp Clin Cancer Res 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 J Exp Clin Cancer Res 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 J Exp Clin Cancer Res 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 t_1/2 (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]	- Collapse 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]	- Collapse 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]	- Collapse 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)

References

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	3 years -20°C powder
Storage	2 years -80°C in solvent
Synonyms	N/A
Smiles	Cl.Cl.COC1=C(OCC2(N)CC2)C=C3N=CC=C(OC4=C(F)C5=C([NH]C(=C5)C)C=C4)C3=C1

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Anlotinib (AL3818) dihydrochloride