Uses
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
Uses
XL184 (Cabozantinib, BMS-907351) is a potent multitargeted VEGFR2, Met, FLT3, Tie2, Kit and Ret inhibitor with IC50 of 0.035, 1.8, 14.4, 14.3 and 4.6 nM for VEGFR2, Met, FLT3, Tie2 and Kit, respectively.
Definition
ChEBI: A dicarboxylic acid diamide that is N-phenyl-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide in which the hydrogen at position 4 on the phenyl ring is substituted by a (6,7-dimethoxyquinolin-4-yl)oxy group. A multi-t
rosine kinase inhibitor, used (as its malate salt) for the treatment of progressive, metastatic, medullary thyroid cancer.
Description
Cabozantinib was approved inNovember 2012 for the treatment of patients
with progressive, unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). Cabozantinib was granted orphan drug
status by the FDA to facilitate development of newtreatment options for patients with MTC. It is a member of a class of tyrosine kinase inhibitors (TKIs) with nanomolar pan-inhibitory activity against VEGFR2, MET, and RET among others. Inhibition of the VEGF pathway has been shown preclinically to initially slow tumor growth, but rapid revascularization is followed by aggressive tumor growth. The MET pathway has been implicated in the development of VEGF resistance, so dual VEGF/MET activity is viewed as desirable.
In addition, mutations in RET play a particular role in MTC, with 25% of
the tumors inheriting a germlinemutation in the proto-oncogene, so multiple
tyrosine kinase inhibition may be viewed as particularly beneficial for the treatment of MTC.
Originator
Exelixis (United States)
General Description
Class:receptor tyrosine kinase; Treatment: MTC; RCC; HCC;
Other name: XL-184, BMS-907351; Elimination half-life = 110 h;
Protein binding > 99.7%
Clinical Use
Cabozantinib (PF-06463922; brand name Cabometyx; Exelixis, Alameda, CA) is
an oral multikinase inhibitor with CNS penetration. It is FDA approved for
use in medullary thyroid cancer and as a second-line agent in advanced renal cell
carcinoma. In vitro studies found it to exhibit excellent activity against both the
wild-type ROS1 fusion and the G2032R and G2026M mutations at concentrations
less than 30?nmol/L—a dose much lower than what is clinically achievable [71, 91].
It has been found to inhibit CD74-ROS1-transformed Ba/F3 cells with more potency
than entrectinib, brigatinib, lorlatinib [92], or foretinib [71].
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration possibly increased by
clarithromycin and erythromycin; concentration
reduced by rifampicin - avoid.
Antiepileptics: concentration possibly reduced
by carbamazepine, fosphenytoin, phenobarbital,
phenytoin and primidone - avoid.
Antipsychotics: avoid with clozapine - increased risk
of agranulocytosis.
Metabolism
Cabozantinib is metabolised mostly by CYP3A4 and, to
a minor extent, by CYP2C9. Both enzymes produce an
N-oxide metabolite.
Cabozantinib is eliminated mainly by the faeces (54%)
and also by the urine (27%).
References
1) Yakes?et al.?(2011),?Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth; Mol. Cancer Ther.,?10?2298
2) You?et al.?(2011),?VEGF and c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer; Cancer Res.,?71?4758
3) Kurzrock?et al.?(2011),?Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor in patients with medullary thyroid cancer; J. Clin. Oncol.,?29?2660
