Uses
TAE 684 is a potent, selective, and efficacious inhibitor of NPM-ALK, a fusion protein that is a key regulator of oncogenic events that drives the survival and proliferation of anaplastic large-cell l
ymphomas.
Uses
Human anaplastic lymphoma kinase (ALK) is an oncogene that is amplified in neuroblastomas and when juxtaposed with various fusion partners, its constitutive kinase activity is associated with the development of a type of anaplastic large cell lymphoma (ALCL). TAE684 is an ALK inhibitor that blocks the proliferation of ALCL-derived and ALK-dependent cell lines with IC50 values of 2-5 nM. When tested against a panel of 35 cells transformed by various tyrosine kinases, TAE684 demonstrated 100- to 1,000-fold selectivity for inhibiting ALK-driven cell proliferation. TAE684 treatment induces cell cycle arrest and apoptosis in ALK-dependent cell lines and has been used to suppress tumor growth in in vivo models of ALK-positive ALCL and neuroblastoma. TAE684 is also reported to inhibit the activity of the Parkinson’s disease-linked leucine-rich repeat kinase 2 (IC50s = 7.8 and 6.1 nM for wild-type and G2019S mutant LRRK2, respectively).[Cayman Chemical]
Definition
ChEBI:5-chloro-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine is a member of piperidines.
Biological Activity
tae684 (nvp-tae684) is a selective inhibitor of alk with ic50 value of 3 nm [1].anaplastic lymphoma kinase (alk) is an enzyme and plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. it has been reported that alk involves in the pathogenesis of various cancers and serves as an important therapeutic target [1, 2].tae684 (nvp-tae684) is a potent alk inhibitor and has a different selectivity with the reported alk inhibitor crizotinib. when tested with alcl cell lines—karpas-299 and su-dhl-1 expressing npm-alk, tae684 (nvp-tae684) inhibited cell proliferation and cell apoptosis in dose-dependent manner [1]. in lung cancer cell lines harboring wild-type, h694r or e1384k mutant alks, tae684 showed effective inhibition on cell proliferation and phospho-y1604 alk expression of h694r or e1384k mutant alk, but also to a degree higher than that of wild-type alk [2].in scidbeige mice model with luciferized karpas-299 cells subcutaneous xenograft, in which the invasion could be detected by a strong bioluminescence signal, oral administration of tae684 (nvp-tae684) caused significant reduction of lymphoma develop and 100- to 1000-fold reduction in luminecsene signal at the dose of 3 and 10 mg/kg. and, the group received tae684 (nvp-tae684) at the dose of 10 mg/kg appeared healthy and showed no signs of compound- or disease-related toxicity [1].it is also reported that tae684 is a potent inhibitor of leucine-rich repeat kinase 2 (lrrk2) with ic50 value of 7.8 nm [3].
in vivo
NVP-TAE684 suppresses lymphomagenesis in two independent models of ALK-positive ALCL and induces regression of established Karpas-299 lymphomas. TAE684 displays appreciable bioavailability and half-life in vivo. TAE684 (1, 3, and 10 mg/kg. p.o.) significantly delays in lymphoma development and shows 100- to 1,000-fold reduction in luminescence signal. The TAE684- (10 mg/kg) treated group appeares healthy and does not display any signs of compound- or disease-related toxicity[1].
References
[1]. galkin, a.v., et al., identification of nvp-tae684, a potent, selective, and efficacious inhibitor of npm-alk. proc natl acad sci u s a, 2007. 104(1): p. 270-5.
[2]. wang, y.w., et al., identification of oncogenic point mutations and hyperphosphorylation of anaplastic lymphoma kinase in lung cancer. neoplasia, 2011. 13(8): p. 704-15.
[3]. zhang, j., et al., characterization of tae684 as a potent lrrk2 kinase inhibitor. bioorg med chem lett, 2012. 22(5): p. 1864-9.
