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849217-68-1 (Cabozantinib)

1

Identification

Cabozantinib Cabozantinib
Name Cabozantinib
Formula C28H24FN3O5
MW 501.51
CAS No. 849217-68-1
EINECS
Smiles O=C(C1(CC1)C(NC2=CC=C(F)C=C2)=O)NC3=CC=C(C=C3)OC4=C5C=C(OC)C(OC)=CC5=NC=C4
Synonyms XL184; BMS-907351; XL-184; XL184; N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
InChI InChI=1S/C28H24FN3O5/c1-35-24-15-21-22(16-25(24)36-2)30-14-11-23(21)37-20-9-7-19(8-10-20)32-27(34)28(12-13-28)26(33)31-18-5-3-17(29)4-6-18/h3-11,14-16H,12-13H2,1-2H3,(H,31,33)(H,32,34)
2

Introduction

Cabozantinib (XL184, BMS-907351) is a potent VEGFR2 inhibitor with IC50 of 0.035 nM and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM, respectively. IC50 value: 0.035 nM [1] Target: VEGFR2 in vitro: XL184 has weak inhibitory activity against RON and PDGFRβ with IC50 of 124 nM and 234 nM, respectivey, and has low activity against FGFR1 with IC50 of 5.294 μM [1].

Background Information

Cabozantinib (also called XL184, BMS-907351 Cometriq [1]), is an inhibitor of multiple receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and rearranged during transfection (RET) [2] [3], with IC50 values of 0.035 nmol/L, 1.3 nmol/L and 5.2 nmol/L to VEGFR2, MET and RET, respectively [4].

RTKs transmit a wide array of extracellular signals for regulating differentiation and proliferation to cells. Ligand binding triggers many events such as autophosphorylation of tyrosine residues and receptor dimerization [5].

TT cell line was a human MTC cell line that had an activating C634W RET mutant and was expressing calcitonin. In this cell line, cabozantinib inhibited the autophosphorylation of RET with an IC50 value of 85 nmol/L. In TT cells grown for 72 h in 10% serum, cabozantinib dose-dependently inhibited cell proliferation with an IC50 value of 94 nmol/L [4].

Administrated with cabozantinib daily orally at doses of 10, 30, or 60 mg/kg, nu/nu mice bearing TT xenograft tumors, showed a significantly inhibited tumor growth compared with vehicle-treated group. At both doses of 30 and 60 mg/kg, cabozantinib caused markedly and significantly reduced circulating calcitonin (75%; p< 0.005) in serum compared with vehicle-treated control animals [4].

References:
[1].  Michael G. Doran, Daniel E. Spratt, John Wongvipat, et al. Cabozantinib Resolves Bone Scans in Tumor-Naїve Mice Harboring Skeletal Injuries. Molecular Imaging, 2014, 13:1-5.
[2].  Rossella Elisei, Martin J. Schlumberger, Stefan P. Müller, et al. Cabozantinib in Progressive Medullary Thyroid Cancer. J. Clin. Oncol., 2013, 31(29):3639-46.
[3].  Razelle Kurzrock, Steven I. Sherman, Douglas W. Ball, et al. Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients with Medullary Thyroid Cancer. J. Clin. Oncol., 2011, 29(19):2660-6.
[4].  Frauke Bentzien, Marcus Zuzow, Nathan Heald, et al. In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer. Thyroid, 2013, 23(12):1569-1577.
[5].  Xianhua Piao, Robert Paulson, Peter van der Geer, et al. Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1. Proc. Natl. Acad. Sci. USA., 1996, 93(25):14665-14669.

......by Apexbio Technology LLC
Cabozantinib is a potent VEGFR2 inhibitor with IC50 of 0.035 nM and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM, respectively. ......by BOC Sciences
This research compound is the s-malate salt form of cabozantinib; please see the other form of cabozantinib, Cat. No. [C-8901], Cabozantinib, Free Base, for further technical information about both of these research compounds. ......by LC Laboratoies
Cabozantinib is a potent multiple RTKs inhibitor that inhibits VEGFR2, c-Met, Kit, Axl and Flt3 with IC50 of 0.035, 1.3, 4.6, 7 and 11.3 nM, respectively. ......by MedChemexpress Co., Ltd.
Cabozantinib (XL 184) is an orally bioavailable, small molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Cabozantinib strongly binds to and inhibits several tyrosine receptor kinases. Specifically, cabozantinib appears to have a strong affinity for the hepatocyte growth factor receptor (Met) and vascular endothelial growth factor receptor 2 (VEGFR2), which may result in inhibition of tumor growth and angiogenesis, and tumor regression. This agent has also been shown to inhibit mast/stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (Flt3) and tyrosine-protein kinase receptor (Tie-2). Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus). Shelf life: >2 years if stored properly Drug formulation: This drug may be formulated in DMSO ......by MedKoo Biosciences, Inc.
Cabozantinib (XL184, BMS-907351) is a potent VEGFR2 inhibitor with IC50 of 0.035 nM and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM in cell-free assays, respectively. ......by Selleck Chemicals LLC
Cabozantinib (XL184, BMS-907351) is a potent VEGFR2 inhibitor with IC50 of 0.035 nM and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM in cell-free assays, respectively. ......by Target Molecule Corp.
Potent VEGFR inhibitor (IC50 = 0.035 nM); also inhibits c-Met, KIT, RET, FLT4, AXL, FLT3, FLT1 and Tie2 (IC50 values are 1.3, 4.6, 5.2, 6, 7, 11.3, 12 and 14.3 nM, respectively). Induces intratumoral hypoxia and apoptosis. Reduces tumor invasion and metastasis in vivo. Antiangiogenic. ......by Tocris Bioscience Inc.
3

Protocol(Only for Reference)

Cell Experiment

Cell lines Human microvascular endothelial (HMVEC) cells
Conditions IC50: 6.7 nM, 7 days
Method HMVEC cells were incubated with VEGF in the presence of cabozantinib and tubule formation visualized by immunostaining for CD31. Cabozantinib inhibited tubule formation with an IC50 value of 6.7 nM with no evidence of cytotoxicity, showing that cabozantinib exerts an antiangiogenic rather than cytotoxic effect.
Source Apexbio Technology LLC
Cell lines ST88-14, STS26T, and MPNST724
Conditions Dissolved in DMSO, final concentrations ~10 μM; 48 hours
Method Cells are exposed to various concentrations of XL184 for 48 hours. Cell growth is determined by MTS assays using CellTiter96 Aqueous Non-Radioactive Cell Proliferation Assay kit. Absorbance is measured at a wavelength of 490 nm, and the absorbance values of treated cells are presented as a percentage of the absorbance of untreated cells.
Source Selleck Chemicals LLC

Animal Experiment

Animal Models Female nu/nu mice implanted with H441 cells
Dosage Form Oral administration, 100 mg/kg, 8 hours
Applications A single 100 mg/kg oral dose of cabozantinib resulted in inhibition of phosphorylation of MET 2 to 8 hours postdose in H441 tumors that harbor constitutively phosphorylated MET. This effect was reversible, as MET phosphorylation returned to basal levels by 48 hours after treatment.
Source Apexbio Technology LLC
Animal Models RIP-Tag2 transgenic mice in a C57BL/6 background with spontaneous pancreatic islet tumors
Dosage ~60 mg/kg
Formulation Suspended at a concentration of 5 mg/mL in sterile saline or water
Administration Oral gavage
Source Selleck Chemicals LLC
4

Physical and Chemical Properties

Appearance:White to off-white solid EBNumber:EB000028888

Storage condition

Store at -20°C by Apexbio Technology LLC
Storage condition:Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years). Stock solution storage:0 - 4 C for short term (days to weeks), or -20 C for long term (months). Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs. by MedKoo Biosciences, Inc.
Store at +4°C by Tocris Bioscience Inc.

Solubility

Soluble in DMSO > 10 mM by Apexbio Technology LLC
DMSO ≥114mg/mL Water <1.2mg/mL Ethanol <1.2mg/mL by MedChemexpress Co., Ltd.
Soluble in DMSO, not in water by MedKoo Biosciences, Inc.
(25°C) * In vitro DMSO 100 mg/mL (199.39 mM); Water<1 mg/mL (<1 mM); Ethanol<1 mg/mL (<1 mM); In vivo 30% Propylene glycol, 5% Tween 80, 65% D5W30 mg/mL by Selleck Chemicals LLC
Soluble to 100 mM in DMSO by Tocris Bioscience Inc.
5

Mechanism and Indication

6

Clinical Information

Product Name Sponsor & Collaborators Indications Start Date End Date Phase
Cabozantinib Exelixis Inc Medullary thyroid cancer 2013/12/31 2017/9/30 Phase 4 Clinical
Cabozantinib Exelixis Inc; PPD Development (S) Pte Ltd Hepatocellular carcinoma 2013/8/31 2016/10/31 Phase 3 Clinical
Cabozantinib Exelixis Inc Renal cell carcinoma 2013/6/30 2016/8/31 Phase 3 Clinical
Cabozantinib Exelixis Inc Hormone refractory prostate cancer 2012/6/30 Phase 3 Clinical
Cabozantinib Exelixis Inc Hormone refractory prostate cancer 2012/1/31 Phase 3 Clinical
Cabozantinib - Launched
7

Safety Data of Cabozantinib

8

Spectral Information

9

Suppliers List

Company Price and Availability Country/Region
Apexbio Technology LLC USA
Apichem Chemical Technology Co., Ltd. China
BOC Sciences
Biochempartner Co., Ltd China
CHEMSCENE, LLC 5mg/USD72();10mg/USD90() USA
LC Laboratoies 10mg/USD42(In stock);25mg/USD61(In stock);50mg/USD93(In stock);100mg/USD142(In stock);200mg/USD249(In stock);500mg/USD539(In stock);1g/USD935(In stock);2g/USD1690(In stock) USA
MedChemexpress Co., Ltd. 5mg/USD72();10mg/USD90() USA
MedKoo Biosciences, Inc. USA
Pure Chemistry Scientific Inc. 50mg/USD33(In stock) USA
Selleck Chemicals LLC 5mg/USD110(In stock);10mg/USD170(In stock);10mM/1mLIn DMSO/USD220(In stock);50mg/USD470(In stock);200mg/USD1470(In stock) USA
Shanghai Biosundrug Science & Technology Co., Ltd. China
Shanghai Goyic Pharmaceutical & Chemical Co., Ltd. China
Shanghai Haoyuan Chemexpress Co., Ltd. 5mg/USD72();10mg/USD90() China
Shanghai Langli Fine Chemical Co., Ltd. China
Taizhou Taifeng Chemical Co., Ltd. China
Target Molecule Corp. 10mg/USD98();50mg/USD198() USA
Tocris Bioscience Inc. USA
Wuhan Sunrise Technology Development Company Limited China
10

Related Products

Other Forms of 849217-68-1

Name CAS No Formula MW
Cabozantinib (S-malate) 1140909-48-3 C32H30FN3O10 635.59

Recommended Compounds in c-Met/HGFR VEGFR FLT3 TAM Receptor c-Kit

Name CAS No Formula MW
Savolitinib 1313725-88-0 C17H15N9 345.3613
MK-8033 (hydrochloride) 1283000-43-0 C25H22ClN5O3S 507.99
c-Met inhibitor 1 1357072-61-7 C17H14N8S 362.41
LY2801653 (dihydrochloride) 1206801-37-7 C30H24Cl2F2N6O3 625.45
LY2801653 1206799-15-6 C30H22F2N6O3 552.53
INCB28060 1029712-80-8 C23H17FN6O 412.42
Crizotinib (hydrochloride) 1415560-69-8 C21H23Cl3FN5O 486.8
NVP-BVU972 1185763-69-2 C20H16N6 340.38
PF-04217903 (methanesulfonate) 956906-93-7 C20H20N8O4S 468.49
MK-2461 917879-39-1 C24H25N5O5S 495.55
C-Kit-IN-1 1225278-16-9 C26H21F2N5O3 489.47
BMS-794833 1174046-72-0 C23H15ClF2N4O3 468.84
MK-2461 (sodium salt, dihydrate) 1170702-81-4 C24H29N5NaO7S+ 554.57
MK-2461 (potassium salt, hydrate) 1170702-82-5 C24H27KN5O6S+ 552.66
EMD-1214063 1100598-32-0 C29H28N6O2 492.57
E-7050 928037-13-2 C33H37F2N7O4 633.69
MK-8033 1001917-37-8 C25H21N5O3S 471.53
Tyrosine kinase inhibitor 1021950-26-4 C31H31FN6O5 586.61
BMS 777607 1025720-94-8 C25H19ClF2N4O4 512.89
MGCD-265 analog 875337-44-3 C26H20FN5O2S2 517.5977

Recommended Compounds in Same Indication

Name CAS No Formula MW
TAK-700 (R-form) 752243-39-3 C18H17N3O2 307.35
Olaparib 763113-22-0 C24H23FN4O3 434.46
KX2-391 897016-82-9 C26H29N3O3 431.53
Bicalutamide 90357-06-5 C18H14F4N2O4S 430.37
Tivantinib 905854-02-6 C23H19N3O2 369.42
Enzalutamide 915087-33-1 C21H16F4N4O2S 464.44
Tivozanib 475108-18-0 C22H19ClN4O5 454.86
Sunitinib 557795-19-4 C22H27FN4O2 398.47
Pazopanib (Hydrochloride) 635702-64-6 C21H24ClN7O2S 473.98
Brivanib (alaninate) 649735-63-7 C22H24FN5O4 441.46
Resminostat 864814-88-0 C16H19N3O4S 349.4
Linsitinib 867160-71-2 C26H23N5O 421.49
Fenretinide 65646-68-6 C26H33NO2 391.55
Retaspimycin 857402-23-4 C31H45N3O8 587.7
Retaspimycin (Hydrochloride) 857402-63-2 C31H46ClN3O8 624.17
Bafetinib 859212-16-1 C30H31F3N8O 576.6154
AT13387 912999-49-6 C24H31N3O3 409.52
Tasquinimod 254964-60-8 C20H17F3N2O4 406.36
Axitinib 319460-85-0 C22H18N4OS 386.47
Sorafenib (Tosylate) 475207-59-1 C28H24ClF3N4O6S 637.03
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Route of Synthesis

12

References

13

More Information

Cabozantinib

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