Sulfatinib, formerly known as surufatinib, is an orally bioavailable, small molecule inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, and the fibroblast growth factor receptor type 1 (FGFR1), with potential antineoplastic and anti-angiogenic activities. Sulfatinib binds to and inhibits FGFR1 and VEGFRs upon oral bioavailable administration, thereby inhibiting signal transduction pathways mediated by FGFR and VEGFR. Tumor cells overexpressing VEGFR/FGFR1 experience a decrease in angiogenesis and tumor cell proliferation as a result. Many types of tumor cells may have elevated expression of FGFR1 and VEGFRs.

Physicochemical Properties

Molecular Formula	C24H28N6O3S
Molecular Weight	480.587
Exact Mass	480.194
Elemental Analysis	C, 59.98; H, 5.87; N, 17.49; O, 9.99; S, 6.67
CAS #	1308672-74-3
Related CAS #	1308672-74-3;1816307-67-1
PubChem CID	52920501
Appearance	White to off-white solid powder
Density	1.3±0.1 g/cm3
Boiling Point	712.9±70.0 °C at 760 mmHg
Flash Point	385.0±35.7 °C
Vapour Pressure	0.0±2.3 mmHg at 25°C
Index of Refraction	1.658
LogP	3.06
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	8
Rotatable Bond Count	10
Heavy Atom Count	34
Complexity	733
Defined Atom Stereocenter Count	0
SMILES	S(C([H])([H])C1C([H])=C([H])C([H])=C(C=1[H])N([H])C1=NC([H])=C([H])C(=N1)OC1C([H])=C([H])C2=C(C=1[H])C([H])=C(C([H])([H])[H])N2[H])(N([H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])[H])(=O)=O
InChi Key	TTZSNFLLYPYKIL-UHFFFAOYSA-N
InChi Code	InChI=1S/C24H28N6O3S/c1-17-13-19-15-21(7-8-22(19)27-17)33-23-9-10-25-24(29-23)28-20-6-4-5-18(14-20)16-34(31,32)26-11-12-30(2)3/h4-10,13-15,26-27H,11-12,16H2,1-3H3,(H,25,28,29)
Chemical Name	N-[2-(dimethylamino)ethyl]-1-[3-[[4-[(2-methyl-1H-indol-5-yl)oxy]pyrimidin-2-yl]amino]phenyl]methanesulfonamide
Synonyms	HMPL012; HMPL012; HMPL 012; surufatinib; Sulfatinib
HS Tariff Code	2934.99.9001
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)

Biological Activity

Targets	VEGFR3 (IC50 = 1 nM); VEGFR1 (IC50 = 2 nM); CSF1R (IC50 = 4 nM); FGFR1 (IC50 = 15 nM); VEGFR2 (IC50 = 24 nM)
ln Vitro	SuLfatinib effectively suppresses VEGF-induced VEGFR2 phosphorylation in HEK293KDR cells and CSF1-stimulated CSF1R phosphorylation in RAW264.7 cells, with IC50s of 2 and 24, respectively. It also inhibits mutations in FGFR1, CSF1R, and VEGFR1, 2, and 3. 79 nanometers. Moreover, SuLfatinib has an IC50<50 nM to suppress HUVEC cell growth that is induced by VEGF or FGF[1]. Furthermore, in CHO cells, it has an IC50 of 6.8 μM, making it a hERG brother [2].
ln Vivo	In animal experiments, VEGF-stimulated VEGFR2 phosphorylation in nude mouse lung tissue was regulated by single-pass SuLfatinib. Furthermore, the suppression of FGFR receptor signaling is indicated by the rise in FGF23 levels in 24 channels after 24 hours. shown robust suppression of angiogenesis via VEGFR and FGFR signaling, as seen by the severe growth inhibition shown in several human xenograft models and the significant reduction of CD31 tumor expression. Sulfatinib demonstrated a moderate reduction in tumor development following a single medication treatment in the syngeneic tumor tumor model CT-26 [1]. The AUC and Cmax in mice were 397 ng/mL and 138 ng/mL, respectively, with a sidewall thickness of 10 mg/kg [1].
Enzyme Assay	The Z-lyte assay kit is utilized to assess the inhibition activity of KDR kinase. Sulfatinib, the test compound, is present in a 384-well plate with varying concentrations, along with 300 ng/mL of recombinant human KDR catalytic domain, 10 μM of ATP, and 1 μM of substrate peptide in the testing system. The total volume is 10 μL. After one hour at room temperature (25°C) on the shaker, the enzyme inhibition process continues. To halt the reaction, 5 μL of stop solution is added[2].
Animal Protocol	Male ICR mice (n = 6 per group; weight 20–30 g) are used to study the phamacokinetics of sulfatinib following a single intravenous and oral dose of 2.5 and 10 mg/kg, respectively. Sulfatinib is dissolved in DMSO (0.25%)-solutol (10%)-ethanol (10%)-physiological saline (797.75%) at a concentration of 0.25 mg/mL for intravenous dosing formulation. Additionally, 0.5% CMC-Na is used to prepare the p.o. Dosing formulation (1 mg/mL). Following intravenous or PO dosage, blood is drawn via the ophthalmic vein at 0 (pre-close), 5, 15, 30 minutes, and 1, 1.5, 2, 4, 8, and 24 hours. The blood is then anticoagulated using heparin-Na. Following centrifugation, plasma samples are separated, and protein is precipitated using an internal standard containing acetonitrilel[2].
References	[1]. PCT Int. Appl. (2011), WO 2011060746 A1 20110526.
Additional Infomation	Surufatinib is under investigation in clinical trial NCT02588170 (Phase III Study of Surufatinib in Treating Advanced Extrapancreatic Neuroendocrine Tumors). Sulfatinib is an orally bioavailable, small molecule inhibitor of vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, and the fibroblast growth factor receptor type 1 (FGFR1), with potential antineoplastic and anti-angiogenic activities. Upon oral administration, sulfatinib binds to and inhibits VEGFRs and FGFR1 thereby inhibiting VEGFR- and FGFR1-mediated signal transduction pathways. This leads to a reduction of angiogenesis and tumor cell proliferation in VEGFR/FGFR1-overexpressing tumor cells. Expression of VEGFRs and FGFR1 may be upregulated in a variety of tumor cell types. Drug Indication Treatment of all conditions included in the category of malignant neoplasms (except central nervous system tumours, haematopoietic and lymphoid tissue neoplasms), Treatment of malignant neoplasms of haematopoietic and lymphoid tissue

Solubility Data

Solubility (In Vitro)

DMSO: ~96 mg/mL (~199.8 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.33 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 20.8 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: ≥ 2.08 mg/mL (4.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.33 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.0808 mL	10.4039 mL	20.8078 mL
	5 mM	0.4162 mL	2.0808 mL	4.1616 mL
	10 mM	0.2081 mL	1.0404 mL	2.0808 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.