TAE684 (NVP-TAE684)

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].

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.

Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.[Pubmed:17185414]

Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):270-5.

Constitutive overexpression and activation of NPM-ALK fusion protein [t(2:5)(p23;q35)] is a key oncogenic event that drives the survival and proliferation of anaplastic large-cell lymphomas (ALCLs). We have identified a highly potent and selective small-molecule ALK inhibitor, NVP-TAE684, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC(50) values between 2 and 10 nM. NVP-TAE684 treatment resulted in a rapid and sustained inhibition of phosphorylation of NPM-ALK and its downstream effectors and subsequent induction of apoptosis and cell cycle arrest. In vivo, NVP-TAE684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. NVP-TAE684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition.

Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684.[Pubmed:21838707]

Biochem J. 2011 Dec 15;440(3):405-13.

Mutations in the kinase domain of ALK (anaplastic lymphoma kinase) have recently been shown to be important for the progression of the childhood tumour neuroblastoma. In the present study we investigate six of the putative reported constitutively active ALK mutations, in positions G1128A, I1171N, F1174L, R1192P, F1245C and R1275Q. Our analyses were performed in cell-culture-based systems with both mouse and human ALK mutant variants and subsequently in a Drosophila melanogaster model system. Our investigation addressed the transforming potential of the putative gain-of-function ALK mutations as well as their signalling potential and the ability of two ATP-competitive inhibitors, Crizotinib (PF-02341066) and NVP-TAE684, to abrogate the activity of ALK. The results of the present study indicate that all mutations tested are of an activating nature and thus are implicated in tumour initiation or progression of neuroblastoma. Importantly for neuroblastoma patients, all ALK mutations used in the present study can be blocked by the inhibitors, although some mutants exhibited higher levels of drug sensitivity than others.

NVP-TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P-glycoprotein (PGP1) function.[Pubmed:26603906]

Br J Pharmacol. 2016 Feb;173(3):613-26.

BACKGROUND AND PURPOSE: Increased expression of P-glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients. EXPERIMENTAL APPROACH: In an effort to search for new chemical entities targeting PGP1-associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies. KEY RESULTS: After screening 500+ kinase inhibitors, we identified NVP-TAE684 as the most effective MDR reversing agent. NVP-TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET-743 or mitoxantrone. NVP-TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1-overexpressing cell lines. NVP-TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors. CONCLUSIONS AND IMPLICATIONS: The application of NVP-TAE684 to restore sensitivity of osteosarcoma MDR cells to the cytotoxic effects of chemotherapeutics will be useful for further study of PGP1-mediated MDR in human cancer and may ultimately benefit cancer patients.

NVP-TAE 684 (TAE 684) is a highly potent and selective ALK inhibitor, which blocks the growth of ALCL-derived and ALK-dependent cell lines with IC50 values between 2 and 10 nM.

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