U.S. Department of Health & Human Services Divider Arrow National Institutes of Health Divider Arrow NCATS

Details

Stereochemistry ACHIRAL
Molecular Formula C28H22F3N7O
Molecular Weight 529.5158
Optical Activity UNSPECIFIED
Defined Stereocenters 0 / 0
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of NILOTINIB

SMILES

CC1=CN(C=N1)C2=CC(=CC(NC(=O)C3=CC=C(C)C(NC4=NC(=CC=N4)C5=CN=CC=C5)=C3)=C2)C(F)(F)F

InChI

InChIKey=HHZIURLSWUIHRB-UHFFFAOYSA-N
InChI=1S/C28H22F3N7O/c1-17-5-6-19(10-25(17)37-27-33-9-7-24(36-27)20-4-3-8-32-14-20)26(39)35-22-11-21(28(29,30)31)12-23(13-22)38-15-18(2)34-16-38/h3-16H,1-2H3,(H,35,39)(H,33,36,37)

HIDE SMILES / InChI

Molecular Formula C28H22F3N7O
Molecular Weight 529.5158
Charge 0
Count
Stereochemistry ACHIRAL
Additional Stereochemistry
Defined Stereocenters 0 / 0
E/Z Centers 0
Optical Activity NONE

Description

Nilotinib (AMN107, trade name Tasigna) is a kinase inhibitor indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included imatinib. Nilotinib is an inhibitor of the Bcr-Abl kinase. Nilotinib binds to and stabilizes the inactive conformation of the kinase domain of Abl protein. In vitro, nilotinib inhibited Bcr-Abl mediated proliferation of murine leukemic cell lines and human cell lines derived from Ph+ CML patients. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from Bcr-Abl kinase mutations, in 32 out of 33 mutations tested. In vivo, nilotinib reduced the tumor size in a murine Bcr-Abl xenograft model. Nilotinib inhibited the autophosphorylation of the following kinases at IC50 values as indicated: Bcr-Abl (20-60 nM), PDGFR (69 nM) and c-Kit (210 nM). Nilotinib is currently being trialed in people with Parkinson's disease, as it appears to be able to halt progression of the disease and even improve their symptoms. The drug also has a number of adverse effects typical of anti-cancer drugs: a headache, fatigue, gastrointestinal problems such as nausea, vomiting, diarrhea and constipation, muscle and joint pain, rash and other skin conditions, flu-like symptoms, and reduced blood cell count. Less typical side effects are those of the cardiovascular system, such as hypertension (high blood pressure), various types of arrhythmia, and prolonged QT interval. Interaction of nilotinib with OATP1B1 and OATP1B3 may alter its hepatic disposition and can lead to transporter mediated drug-drug interactions. Nilotinib is an inhibitor of OATP-1B1 transporter but not for OATP-1B3. Main metabolic pathways identified in healthy subjects are oxidation and hydroxylation. Nilotinib is the main circulating component in the serum. None of the metabolites contributes significantly to the pharmacological activity of nilotinib.

CNS Activity

Originator

Approval Year

PubMed

PubMed

TitleDatePubMed
[Novel inhibitors of Bcr-Abl].
2006
[New strategies to overcome imatinib resistance in treatment for chronic myelocytic leukemia].
2006 Aug
Gateways to clinical trials.
2006 Dec
Beyond imatinib: second generation c-KIT inhibitors for the management of gastrointestinal stromal tumors.
2006 Nov
Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs.
2007 Apr 15
Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders.
2007 Aug
Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability.
2007 Aug
Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor.
2007 Aug 15
Roots of imatinib resistance: a question of self-renewal?
2007 Aug-Oct
Impaired fasting glucose level as metabolic side effect of nilotinib in non-diabetic chronic myeloid leukemia patients resistant to imatinib.
2007 Dec
Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors.
2007 Dec 1
Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets.
2007 Dec 1
What is new in chronic myeloid leukaemia?
2007 Feb
Important therapeutic targets in chronic myelogenous leukemia.
2007 Feb 15
[Molecular targeting therapy for chronic myeloid leukemia].
2007 Jan
New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance.
2007 Jan
Chronic Myeloid Leukaemia in The 21st Century.
2007 Jan
Gateways to clinical trials.
2007 Jan-Feb
Drugs offer new hope for patients with CML who are resistant to imatinib.
2007 Jul
Drug evaluation: Nilotinib - a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond.
2007 Jul
The tyrosine kinase inhibitor AMN107 (Nilotinib) exhibits off-target effects in lymphoblastic cell lines.
2007 Jul
Successful allogeneic stem cell transplantation in second chronic-phase CML induced by the tyrosine kinase inhibitor nilotinib (AMN107) after blast crisis under imatinib.
2007 Jul
Monosomy 7 in t(9;22)-negative cells during nilotinib therapy in an imatinib-resistant chronic myeloid leukemia case.
2007 Jul 15
Novel tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with chronic myeloid leukemia: no evidence for increased transplant-related toxicity.
2007 Jul 15
BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia.
2007 Jul 19
Gateways to clinical trials.
2007 Jun
[Novel anti-CML agents beyond imatinib].
2007 Jun
Imatinib and nilotinib induce apoptosis of chronic myeloid leukemia cells through a Bim-dependant pathway modulated by cytokines.
2007 Jun
Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells.
2007 Jun
Current and emerging treatment options in chronic myeloid leukemia.
2007 Jun 1
Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study.
2007 Jun 1
High-performance liquid chromatography method with ultraviolet detection for the quantification of the BCR-ABL inhibitor nilotinib (AMN107) in plasma, urine, culture medium and cell preparations.
2007 Jun 1
Gateways to clinical trials.
2007 Mar
Optimal management of patients with newly diagnosed chronic phase chronic myeloid leukemia in 2007.
2007 Mar
Bcr-Abl kinase domain mutations and the unsettled problem of Bcr-AblT315I: looking into the future of controlling drug resistance in chronic myeloid leukemia.
2007 Mar
Emerging safety issues with imatinib and other Abl tyrosine kinase inhibitors.
2007 Mar
Emerging strategies for the treatment of mutant Bcr-Abl T315I myeloid leukemia.
2007 Mar
Gateways to clinical trials.
2007 May
Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells.
2007 May 1
UGT1A1 promoter polymorphism increases risk of nilotinib-induced hyperbilirubinemia.
2007 Nov
Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors.
2007 Nov
Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance.
2007 Nov 15
Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells.
2007 Oct
Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia.
2007 Oct 1
How I treat chronic myeloid leukemia in the imatinib era.
2007 Oct 15
Crystal structure of the T315I mutant of AbI kinase.
2007 Sep
Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency.
2007 Sep
The multikinase inhibitor sorafenib induces apoptosis in highly imatinib mesylate-resistant bcr/abl+ human leukemia cells in association with signal transducer and activator of transcription 5 inhibition and myeloid cell leukemia-1 down-regulation.
2007 Sep
A critical appraisal of conventional and investigational drug therapy in patients with hypereosinophilic syndrome and clonal eosinophilia.
2007 Sep 1
Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia.
2007 Sep 15
Patents

Patents

Sample Use Guides

In Vivo Use Guide
400 mg orally twice daily, approximately 12 hours apart and should not be taken with food.
Route of Administration: Oral
In Vitro Use Guide
AMN107 (nilotinib) inhibited proliferation of Ba/F3 cells expressing G250E, E255K(V), F317L, M351T, F486S, M244V, L248R, Q252H, Y253H, E255K, E279K, E282D, V289S, and L348M Bcr-Abl mutants at <1 uM concentrations.
Substance Class Chemical
Created
by admin
on Mon Oct 21 20:51:38 UTC 2019
Edited
by admin
on Mon Oct 21 20:51:38 UTC 2019
Record UNII
F41401512X
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
NILOTINIB
DASH   EMA EPAR   HSDB   INN   MART.   USAN   VANDF   WHO-DD  
INN   USAN  
Official Name English
NILOTINIB [USAN]
Common Name English
NILOTINIB [EMA EPAR]
Common Name English
NILOTINIB [VANDF]
Common Name English
BENZAMIDE, 4-METHYL-N-(3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL)-3-((4-(3-PYRIDINYL)-2-PYRIMIDINYL)AMINO)-
Systematic Name English
NILOTINIB [HSDB]
Common Name English
NILOTINIB [INN]
Common Name English
NILOTINIB [WHO-DD]
Common Name English
AMN107
Code English
4-METHYL-N-(3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL)-3-((4-PYRIDIN-3-YLPYRIMIDIN-2-YL)AMINO)BENZAMIDE
Systematic Name English
NILOTINIB [MART.]
Common Name English
AMN 107
Code English
AMN-107
Code English
NILOTINIB [MI]
Common Name English
Classification Tree Code System Code
WHO-ATC L01XE08
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
LIVERTOX 685
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
NDF-RT N0000175605
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
FDA ORPHAN DRUG 237307
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
NDF-RT N0000175076
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
WHO-VATC QL01XE08
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
EU-Orphan Drug EU/3/06/375
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
NCI_THESAURUS C155700
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
EMA ASSESSMENT REPORTS TASIGNA ( AUTHORIZED: LEUKEMIA , MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE)
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
FDA ORPHAN DRUG 220806
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
Code System Code Type Description
IUPHAR
5697
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
DRUG BANK
DB04868
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
ChEMBL
CHEMBL255863
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
INN
8654
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
LactMed
641571-10-0
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
HSDB
641571-10-0
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
EVMPD
SUB25225
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
RXCUI
662281
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY RxNorm
CAS
641571-10-0
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
PUBCHEM
644241
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
EPA CompTox
641571-10-0
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
NCI_THESAURUS
C48375
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
MERCK INDEX
M11754
Created by admin on Mon Oct 21 20:51:38 UTC 2019 , Edited by admin on Mon Oct 21 20:51:38 UTC 2019
PRIMARY
Related Record Type Details
TARGET -> INHIBITOR
TRANSPORTER -> SUBSTRATE
TRANSPORTER -> INHIBITOR
RESISTANT TARGET->INHIBITOR
TARGET -> INHIBITOR
TRANSPORTER -> SUBSTRATE
TRANSPORTER -> SUBSTRATE
TRANSPORTER -> SUBSTRATE
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
SALT/SOLVATE -> PARENT
TARGET -> INHIBITOR
INHIBITOR
RESISTANT TARGET->INHIBITOR
TARGET -> INHIBITOR
TRANSPORTER -> INHIBITOR
TRANSPORTER -> SUBSTRATE
TARGET -> INHIBITOR
TARGET -> INHIBITOR
TRANSPORTER -> SUBSTRATE
TARGET -> INHIBITOR
Related Record Type Details
METABOLITE ACTIVE -> PARENT
METABOLITE -> PARENT
FECAL
METABOLITE -> PARENT
FECAL
Related Record Type Details
ACTIVE MOIETY