NILOTINIB HYDROCHLORIDE ANHYDROUS

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H22F3N7O.ClH
Molecular Weight	565.977
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of NILOTINIB HYDROCHLORIDE ANHYDROUS

Structure Search

SMILES

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

InChI

InChIKey=VTGGYCCJUPYZSX-UHFFFAOYSA-N

InChI=1S/C28H22F3N7O.ClH/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);1H

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/16721371 | https://www.ncbi.nlm.nih.gov/pubmed/19920925

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

Targets

Primary Target	Pharmacology	Condition	Potency
Bcr/Abl fusion protein 16 Target ID: CHEMBL2096618 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19920925	Inhibitor 8297		0.33 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) 8 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022068s023lbl.pdf	Primary		Approved 8429	TASIGNA Approved Use Tasigna is a kinase inhibitor indicated for: The treatment of newly diagnosed adult patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The treatment of chronic phase (CP) and accelerated phase (AP) Ph+ CML in adult patients resistant to or intolerant to prior therapy that included imatinib. (1.2) 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) Launch Date 2007

C_max

Value	Dose	Analyte	Population
1550 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
2300 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
3320 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121	600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
6010 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121	600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
2190 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	800 mg 1 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
2490 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	1200 mg 1 times / day steady-state, oral dose: 1200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
403 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
402.715 ng/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544	230 mg/m^2 single, oral dose: 230 mg/m^2 route of administration: oral experiment type: single co-administered:	NILOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: food status:
405.111 ng/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544	230 mg/m^2 single, oral dose: 230 mg/m^2 route of administration: oral experiment type: single co-administered:	NILOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: food status:
1360 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30179260	300 mg 2 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: FEMALE / MALE food status: FASTED
1595 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30179260	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Analyte	Population
12700 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
18200 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
24500 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121	600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
43100 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19924121	600 mg 2 times / day steady-state, oral dose: 600 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB serum	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: HIGH-FAT
26600 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	800 mg 1 times / day steady-state, oral dose: 800 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
28000 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	1200 mg 1 times / day steady-state, oral dose: 1200 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
4480 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	50 mg 1 times / day steady-state, oral dose: 50 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB unknown	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
14383.076 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544	230 mg/m^2 2 times / day steady, oral dose: 230 mg/m^2 route of administration: oral experiment type: steady co-administered:	NILOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: food status:
15129.182 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544	230 mg/m^2 2 times / day steady, oral dose: 230 mg/m^2 route of administration: oral experiment type: steady co-administered:	NILOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: food status:
2795.78199999999 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544	230 mg/m^2 single, oral dose: 230 mg/m^2 route of administration: oral experiment type: single co-administered:	NILOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: food status:
3393.296 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544	230 mg/m^2 single, oral dose: 230 mg/m^2 route of administration: oral experiment type: single co-administered:	NILOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: food status:
4160.969 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544	230 mg/m^2 single, oral dose: 230 mg/m^2 route of administration: oral experiment type: single co-administered:	NILOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: food status:
5707.368 ng*h/mL Clinical Trial https://clinicaltrials.gov/ct2/show/NCT01077544	230 mg/m^2 single, oral dose: 230 mg/m^2 route of administration: oral experiment type: single co-administered:	NILOTINIB plasma	Homo sapiens population: unhealthy age: Children sex: food status:
11865 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30179260	300 mg 2 times / day steady-state, oral dose: 300 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: FEMALE / MALE food status: FASTED
13656 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/30179260	400 mg 2 times / day steady-state, oral dose: 400 mg route of administration: Oral experiment type: STEADY-STATE co-administered:	NILOTINIB plasma	Homo sapiens population: UNHEALTHY age: UNKNOWN sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
1.6% OTHER GOV https://www.ema.europa.eu/en/documents/scientific-discussion/tasigna-epar-scientific-discussion_en.pdf			NILOTINIB plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
400 mg 2 times / day steady, oral Recommended Dose: 400 mg, 2 times / day Route: oral Route: steady Dose: 400 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 56 years (range: 26-85 years) n = 132 Health Status: unhealthy Condition: Philadelphia chromosome positive chronic myelogenous leukemia - chronic phase ((CML-CP) Age Group: 56 years (range: 26-85 years) Sex: M+F Population Size: 132 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	Disc. AE: Thrombocytopenia, Neutropenia... AEs leading to discontinuation/dose reduction: Thrombocytopenia (5 patients) Neutropenia (1 patient) Bilirubin increased (2 patients) Hepatotoxicity (2 patients) Skin rash (1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
600 mg 2 times / day steady, oral MTD Dose: 600 mg, 2 times / day Route: oral Route: steady Dose: 600 mg, 2 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19924121/	unhealthy, 56.2 ± 15.3 years n = 18 Health Status: unhealthy Condition: CML: blastic phase, accelerated phase, and chronic phase) \| Ph-positive ALL Age Group: 56.2 ± 15.3 years Sex: M+F Population Size: 18 Sources: https://pubmed.ncbi.nlm.nih.gov/19924121/	Sources: https://pubmed.ncbi.nlm.nih.gov/19924121/
400 mg 2 times / day steady, oral Recommended Dose: 400 mg, 2 times / day Route: oral Route: steady Dose: 400 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	unhealthy, 59 years (range: 22-79 years) n = 64 Health Status: unhealthy Condition: Philadelphia chromosome positive chronic myelogenous leukemia - accelerated phase (CML-AP) Age Group: 59 years (range: 22-79 years) Sex: M+F Population Size: 64 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf	Disc. AE: Rash, Pancreatitis... AEs leading to discontinuation/dose reduction: Rash (1 patient) Pancreatitis (1 patient) Myocardial infarction (1 patient) Thrombocytopenia (grade 3, 1 patient) Neutropenia (grade 3, 1 patient) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_MedR_P2.pdf
1200 mg 1 times / day steady, oral Dose: 1200 mg, 1 times / day Route: oral Route: steady Dose: 1200 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	unhealthy, 60 years (range: 15-83 years) n = 10 Health Status: unhealthy Condition: Ph-positive ALL \| CML Age Group: 60 years (range: 15-83 years) Sex: M+F Population Size: 10 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235	Other AEs: Rash, Fatigue... Other AEs: Rash (grade 3-4, 3%) Fatigue (grade 3-4, 3%) Bilirubin total increased (grade 3-4, 3%) Conjugated bilirubin level increased (grade 3-4, 3%) Bilirubin unconjugated increased (grade 3-4, 6%) Lipase increased (grade 3-4, 3%) ALT increased (grade 3-4, 9%) Aspartate aminotransferase increased (grade 3-4, 9%) Thrombocytopenia (grade 3-4, 17%) Neutropenia (grade 3-4, 14%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf https://pubmed.ncbi.nlm.nih.gov/16775235

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 781 substrate 1737	inducer 389 inhibitor 1767 substrate 1037	inhibitor 1852	inhibitor 1612

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP3A4/5 278 CYP2C8 911 CYP2C19 1478 P-gp 1461 UGT1A1 204	P-gp 1537 MRP1 107 CYP2J2 56 CYP1A2 1054 CYP2C8 693 OCT1 327	CYP2B6 547 CYP2C8 168 CYP1A1 108 CYP1A2 701 UGT1A1 69 CYP2C19 293 P-gp 257 MRP2 111

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
CYP2C19 1553	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
MRP2 475	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
P-gp 1650	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
UGT1A1 254	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	weak
P-gp 1650	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [IC50 1.7 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 0.132 uM]
UGT1A1 254	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 0.19 uM]	yes (pharmacogenomic study) Comment: The (TA)7/(TA)7 genotype was associated with a statistically significant increase in risk of nilotinib-induced hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf
CYP2C8 965	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 0.236 uM]
CYP3A4/5 335	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 0.448 uM]	yes (co-administration study) Comment: nilotinib increased auc of midazolam by 30% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf
CYP2D6 1891	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 1.46 uM]
CYP2C19 1553	inhibitor 3277 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes [Ki 3.82 uM]
CYP1A1 218	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP1A2 1692	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP2B6 1001	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP2C8 965	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP2C9 1819	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes
CYP3A4 1925	inducer 1573 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1737	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	major	yes (co-administration study) Comment: ketoconazole increased auc of nilotinib by 3x, cmax by 84% Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf
CYP1A2 1054	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	minor
CYP2C8 693	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	minor
CYP2C9 1037	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	minor
CYP2J2 56	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	minor
MRP1 107	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
OCT1 327	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	no
P-gp 1537	substrate 3367 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_ClinPharmR.pdf	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1647	inhibitor 1626 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022068s000_PharmR_P1.pdf

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:52172	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:52172
ChemicalBook	CB5966228	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB5966228
MolPort	MolPort-003-987-089	https://www.molport.com/shop/molecule-link/MolPort-003-987-089
Selleck Chemicals	Nilotinib	http://www.selleckchem.com/products/Nilotinib.html
ZINC	ZINC000006716957	http://zinc15.docking.org/substances/ZINC000006716957
eMolecules	10645209	https://www.emolecules.com/cgi-bin/more?vid=10645209

PubMed

Title	Date	PubMed
[New strategies to overcome imatinib resistance in treatment for chronic myelocytic leukemia].	2006 Aug	17236546
Tyrosine kinase inhibitors: the next generation.	2006 Aug	16900596
American Society of Clinical Oncology--42nd annual meeting. Poster presentations on leukemia and cytotoxic chemotherapy. 2-6 June 2006, Atlanta, GA, USA.	2006 Aug	16871453
Gateways to clinical trials.	2006 Dec	17235418
Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity.	2006 Dec	17087936
Novel treatment strategies for chronic myeloid leukemia.	2006 Dec 1	17106016
New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance.	2006 Dec 19	17179059
Activity of AMN107 in gleevec-resistant leukemia.	2006 Jan	16924763
Emerging drugs in chronic myelogenous leukaemia.	2006 Nov	17064224
Novel tyrosine kinase inhibitors in chronic myelogenous leukemia.	2006 Nov	16988578
Gateways to clinical trials.	2006 Oct	17136234
Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugs.	2007 Apr 15	17409347
Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure.	2007 Apr 15	17342766
Kit: molecule of interest for the diagnosis and treatment of mastocytosis and other neoplastic disorders.	2007 Aug	17691909
Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability.	2007 Aug	17614824
Sorafenib inhibits the imatinib-resistant KITT670I gatekeeper mutation in gastrointestinal stromal tumor.	2007 Aug 15	17699867
Impaired fasting glucose level as metabolic side effect of nilotinib in non-diabetic chronic myeloid leukemia patients resistant to imatinib.	2007 Dec	17382388
Dynamics of BCR-ABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors.	2007 Dec 1	17785585
Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets.	2007 Dec 1	17720881
What is new in chronic myeloid leukaemia?	2007 Feb	17373424
[Innovation of clinical trials for anti-cancer drugs in Japan--proposals from academia with special reference to the development of novel Bcr-Abl/Lyn tyrosine kinase inhibitor INNO-406 (NS-187) for imatinib-resistant chronic myelogenous leukemia].	2007 Feb	17301549
KIT mutations in GIST.	2007 Feb	17208434
Simultaneous determination of AMN107 and Imatinib (Gleevec, Glivec, STI571) in cultured tumour cells using an isocratic high-performance liquid chromatography procedure with UV detection.	2007 Feb 1	16962394
Important therapeutic targets in chronic myelogenous leukemia.	2007 Feb 15	17317816
Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia.	2007 Jan	17164530
MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation.	2007 Jan 15	16990603
Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure.	2007 Jan 15	16990591
Gateways to clinical trials.	2007 Jan-Feb	17344945
Drug evaluation: Nilotinib - a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond.	2007 Jul	17642017
Monosomy 7 in t(9;22)-negative cells during nilotinib therapy in an imatinib-resistant chronic myeloid leukemia case.	2007 Jul 15	17656263
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	17559140
BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia.	2007 Jul 19	17634461
Gateways to clinical trials.	2007 Jun	17805439
Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells.	2007 Jun	17519960
Identification of BCR-ABL point mutations conferring resistance to the Abl kinase inhibitor AMN107 (nilotinib) by a random mutagenesis study.	2007 Jun 1	17303698
Gateways to clinical trials.	2007 Mar	17440629
Optimal management of patients with newly diagnosed chronic phase chronic myeloid leukemia in 2007.	2007 Mar	17382023
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	17382021
Emerging strategies for the treatment of mutant Bcr-Abl T315I myeloid leukemia.	2007 Mar	17382017
Emerging therapeutic options for Philadelphia-positive acute lymphocytic leukemia.	2007 Mar	17355221
Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias.	2007 Mar 1	17068153
Gateways to clinical trials.	2007 May	17609744
Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells.	2007 May 1	17213283
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	17403535
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	17715389
Synergistic antiproliferative effects of KIT tyrosine kinase inhibitors on neoplastic canine mast cells.	2007 Oct	17681669
Crystal structure of the T315I mutant of AbI kinase.	2007 Sep	17718712
Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency.	2007 Sep	17710227
A critical appraisal of conventional and investigational drug therapy in patients with hypereosinophilic syndrome and clonal eosinophilia.	2007 Sep 1	17654661
Tyrosine kinase inhibitors for the treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia.	2007 Sep 15	17701954

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.

Name

Type

Language

NILOTINIB HYDROCHLORIDE ANHYDROUS

Common Name

English

BENZAMIDE, 4-METHYL-N-(3-(4-METHYL-1H-IMIDAZOL-1-YL)-5-(TRIFLUOROMETHYL)PHENYL)-3-((4-(3-PYRIDINYL)-2-PYRIMIDINYL)AMINO)-, HYDROCHLORIDE (1:1)

Systematic Name

English

NILOTINIB HYDROCHLORIDE [ORANGE BOOK]

Common Name

English

Nilotinib hydrochloride [WHO-DD]

Common Name

English

NILOTINIB HYDROCHLORIDE

Common Name

English

NILOTINIB HYDROCHLORIDE [VANDF]

Common Name

English

NILOTINIB (AS HYDROCHLORIDE)

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C155700