TAE-684

Details

Stereochemistry	ACHIRAL
Molecular Formula	C30H40ClN7O3S
Molecular Weight	614.202
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

COC1=CC(=CC=C1NC2=NC=C(Cl)C(NC3=CC=CC=C3S(=O)(=O)C(C)C)=N2)N4CCC(CC4)N5CCN(C)CC5

InChI

InChIKey=QQWUGDVOUVUTOY-UHFFFAOYSA-N

InChI=1S/C30H40ClN7O3S/c1-21(2)42(39,40)28-8-6-5-7-26(28)33-29-24(31)20-32-30(35-29)34-25-10-9-23(19-27(25)41-4)37-13-11-22(12-14-37)38-17-15-36(3)16-18-38/h5-10,19-22H,11-18H2,1-4H3,(H2,32,33,34,35)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17185414 | https://www.ncbi.nlm.nih.gov/pubmed/22335897
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20207848

TAE-684 is Novartis’ first-generation inhibitor of the enzyme anaplastic lymphoma kinase with IC50 of 3 nM in a cell-free assay, which blocked the growth of ALCL-derived and ALK-dependent cell lines with IC50 values between 2 and 10 nM. TAE-684 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, TAE-684 suppressed lymphomagenesis in two independent models of ALK-positive ALCL and induced regression of established Karpas-299 lymphomas. TAE-684 also induced down-regulation of CD30 expression, suggesting that CD30 may be used as a biomarker of therapeutic NPM-ALK kinase activity inhibition. TAE-684 is also a potent inhibitor of LRRK2 kinase activity (IC(50) of 7.8nM against wild-type LRRK2. TAE-684 development was discontinued, as it formed potentially harmful protein adducts in the body.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
ALK tyrosine kinase receptor 24 Target ID: CHEMBL4247 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17185414 \| https://www.ncbi.nlm.nih.gov/pubmed/25461320	Inhibitor 8504		3.0 nM [IC50]
Leucine-rich repeat serine/threonine-protein kinase 2 4 Target ID: CHEMBL1075104 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22335897	Inhibitor 8504		7.8 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Lymphoma 60 Sources: http://adisinsight.springer.com/drugs/800026617	Primary		Preclinical	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.	2013-07-25	23742252
Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells.	2012-12-13	22286764
Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer.	2012-11-15	22843788
Differential protein stability and ALK inhibitor sensitivity of EML4-ALK fusion variants.	2012-09-01	22912387
Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor resistance in EML4-ALK lung cancer cells.	2012-07-01	22553343
Development of treatment strategies for advanced neuroblastoma.	2012-06	22588779
Activating ALK mutations found in neuroblastoma are inhibited by Crizotinib and NVP-TAE684.	2011-12-15	21838707
ALK mutations conferring differential resistance to structurally diverse ALK inhibitors.	2011-12-01	21948233
Crizotinib-resistant mutants of EML4-ALK identified through an accelerated mutagenesis screen.	2011-12	22034911
Comprehensive analysis of kinase inhibitor selectivity.	2011-10-30	22037378
A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.	2011-09-15	21791641
Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action.	2011-06	21233844
Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.	2011-05-03	21502504
The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.	2010-12-15	21030459
Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry.	2010-11-24	21095574
Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.	2007-01-02	17185414

Patents

Sample Use Guides

In Vivo Use Guide

Mice: TAE-684 was administered at 1, 3, and 10 mg/kg once daily by oral gavage to mice

Route of Administration: Oral

In Vitro Use Guide

TAE-684 potently inhibits the proliferation of Ba/F3 NPM-ALK cells with IC50 of 3 nM, without affecting the survival of Ba/F3 cells even at 1 uM. TAE-684 also inhibits proliferation of NPM-ALK-expressing human ALCL cell lines including Karpas-299 and SU-DHL-1 with IC50 of 2–5 nM.

Name

Type

Language

NVP-TAE 684

Preferred Name

English

TAE-684

Common Name

English

NVT-TAE-684

Code

English

NVP-TAE684

Code

English

5-CHLORO-N4-(2-(ISOPROPYLSULFONYL)PHENYL)-N2-(2-METHOXY-4-(4-(4-METHYLPIPERAZIN-1-YL)PIPERIDIN-1-YL)PHENYL)PYRIMIDINE-2,4-DIAMINE

Systematic Name

English

Code System Code Type Description

NCI_THESAURUS

C171615