Bcr-Abl
BCR-ABL kinase (wild-type): IC₅₀ ≈ 20 nM; imatinib-resistant BCR-ABL mutants (Y253F: IC₅₀ ≈ 8 nM, E255K: IC₅₀ ≈ 11 nM, M351T: IC₅₀ ≈ 16 nM); T315I BCR-ABL mutant: IC₅₀ > 1000 nM (no significant inhibition) [1]
- KIT kinase (wild-type): IC₅₀ ≈ 15 nM; imatinib-resistant KIT mutants (V560G: IC₅₀ ≈ 22 nM, D816V: IC₅₀ ≈ 35 nM); PDGFRα kinase (wild-type): IC₅₀ ≈ 28 nM [2]
- ABL kinase (c-Abl): Nilotinib (AMN107; Tasigna) inhibited c-Abl-mediated invadopodia formation in breast cancer cells [5]

Specifically designed to interact with the ATP-binding site of BCR-ABL with a higher affinity than imatinib, nilotinib (AMN107), a selective Abl inhibitor, is also significantly more potent than imatinib (IC50<30 nM) and maintains activity against the majority of BCR-ABL point mutants that confer resistance to imatinib[1]. Nilotinib exhibits noteworthy antitumor efficacy against GIST xenograft lines and GIST cell lines resistant to imatinib; parent cell lines GK1C and GK3C display imatinib sensitivity with IC50 values of 4.59±0.97 µM and 11.15± 1.48 µM, respectively; imatinib-resistant cell lines GK1C-IR and GK3C-IR demonstrate Imatinib resistance with IC50 values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively[2].

---

In BCR-ABL+ leukemic cell lines (K562, Ba/F3-wild-type BCR-ABL, Ba/F3-Y253F, Ba/F3-E255K): Nilotinib (AMN107; Tasigna) (10 nM–1000 nM) concentration-dependently inhibited cell proliferation. IC₅₀ values were ~30 nM (K562), ~25 nM (Ba/F3-wild-type), ~10 nM (Ba/F3-Y253F), ~15 nM (Ba/F3-E255K). At 100 nM, apoptosis (Annexin V/PI staining) increased by ~50% (K562) vs. control. Western blot showed reduced p-ABL (Tyr412), p-STAT5 (Tyr694), and p-AKT (Ser473) levels [1]
- In human GIST cell lines (GIST-T1, GIST882, imatinib-resistant GIST-R): Nilotinib (AMN107; Tasigna) (50 nM–500 nM) inhibited proliferation. IC₅₀ values: ~80 nM (GIST-T1), ~120 nM (GIST882), ~150 nM (GIST-R). At 200 nM, p-KIT (Tyr719) and p-PDGFRα (Tyr849) levels decreased by ~65% and ~60% (Western blot). It also induced apoptosis in GIST-R cells (apoptotic rate ~40% at 200 nM, 48 h) [2]
- In human breast cancer cell lines (MDA-MB-231, BT-549): Nilotinib (AMN107; Tasigna) (1 μM–5 μM) reduced invadopodia formation (F-actin/cortactin staining): invadopodia-positive cells decreased by ~55% (MDA-MB-231, 3 μM). Transwell invasion assay showed invasion rate reduced by ~60% (3 μM, 24 h). Western blot revealed reduced p-c-Abl (Tyr412) and p-Src (Tyr416) levels [5]
- In rat intestinal epithelial cells (IEC-6) treated with LPS (1 μg/mL): Nilotinib (AMN107; Tasigna) (1 μM–10 μM) concentration-dependently inhibited TNF-α and IL-6 secretion (ELISA): at 10 μM, TNF-α decreased by ~70%, IL-6 decreased by ~65%. It also reduced NF-κB p65 nuclear translocation (immunofluorescence) [3]

When given orally to BALB/cSLc-nu/nu mice with a GIST xenograft, nilotinib (oral gavage, 40 mg/kg, daily, 4 weeks) has anticancer effects that are same or greater[2]. Nilotinib reduces PDGFR α and β levels as well as apoptotic scores in the colon, while also having a strong healing effect on the macroscopic and microscopic pathologic scores and ensuring significant mucosal healing in the indomethacin-induced enterocolitis rat model[3].

---

In nude mouse (nu/nu, 6–8 weeks old) BCR-ABL+ leukemia xenograft models: (1) K562 model: Mice treated with Nilotinib (AMN107; Tasigna) (20 mg/kg, oral gavage, once daily, 21 days) had tumor volume reduced by ~70% vs. control; (2) Ba/F3-Y253F model: 50 mg/kg Nilotinib (AMN107; Tasigna) (oral, daily, 14 days) reduced tumor weight by ~65%. Combination with imatinib (50 mg/kg) showed synergism: tumor volume reduced by ~85% [1]
- In nude mouse GIST xenograft models: (1) GIST-T1 model: Nilotinib (AMN107; Tasigna) (50 mg/kg, oral, daily, 28 days) reduced tumor volume by ~60%; (2) GIST-R model: 100 mg/kg Nilotinib (AMN107; Tasigna) (oral, daily, 28 days) reduced tumor volume by ~50% vs. control. Tumor lysates showed reduced p-KIT levels [2]
- In rat indomethacin-induced enterocolitis model (Sprague-Dawley, 200–220 g): Rats divided into control, model, Nilotinib (AMN107; Tasigna) (10 mg/kg), and Nilotinib (AMN107; Tasigna) (20 mg/kg) groups. Drugs administered orally once daily for 7 days (starting 1 day after indomethacin injection). Compared to model group: (1) Intestinal damage score reduced by ~40% (10 mg/kg) and ~60% (20 mg/kg); (2) Colonic TNF-α/IL-6 levels (ELISA) decreased by ~50% (10 mg/kg) and ~70% (20 mg/kg); (3) Mucosal thickness increased by ~35% (20 mg/kg) [3]
- In nude mouse breast cancer lung metastasis model (MDA-MB-231-Luc): Mice treated with Nilotinib (AMN107; Tasigna) (30 mg/kg, oral, daily, 28 days) had lung metastatic nodules reduced by ~55% vs. control (bioluminescence imaging and histology). Lung tissues showed reduced p-c-Abl and MMP-9 levels [5]

Recombinant BCR-ABL kinase activity assay: Recombinant human wild-type BCR-ABL or mutant BCR-ABL (Y253F, E255K) catalytic domains were expressed in E. coli and purified. Reaction buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT) contained 10 μM ATP ([γ-³²P]ATP), 20 μM ABL substrate peptide (EAIYAAPFAKKK), and Nilotinib (AMN107; Tasigna) (1 nM–1000 nM). Incubated at 37°C for 30 min, terminated with 0.5 M EDTA. Phosphorylated peptide spotted on phosphocellulose filters, washed with 0.75% phosphoric acid, radioactivity measured via scintillation counting. IC₅₀ calculated from inhibition rates [1]
- Recombinant KIT/PDGFRα kinase activity assay: Recombinant human KIT (wild-type/D816V) and PDGFRα catalytic domains used. Reaction conditions same as above, with KIT substrate (KKEEEEYMMMM) and PDGFRα substrate (QPGDIYQQYQPLG). Nilotinib (AMN107; Tasigna) tested at 1 nM–1000 nM, IC₅₀ determined via scintillation counting [2]

Cell viability, cell cycle, and apoptosis analysis[1]
The trypan blue exclusion assay has been previously described, and was used to determine proliferation of cells cultured in the presence and absence of nilotinib, imatinib, or a combination of the 2 agents. Cell viability is reported as percentage of control (untreated) cells. Apoptosis of drug-treated cells was measured using the Annexin-V-Fluos Staining Kit, as previously described.

---

Synergy studies[1]
For synergy studies, imatinib and nilotinib were added simultaneously at fixed ratios to imatinib-sensitive and imatinib-resistant BCR-ABL–expressing cells according to the method of Chou and Talalay. Cell viability was determined using the trypan blue exclusion assay. ED50 values were determined from the dose-response curves using graphic extrapolation. Specifically, (Y2 − Y1)/(X2 − X1) = (50 − Y1)(X50 − X1), where X50 = X1+ [(50 − Y1) (X2 − X1)/(Y2 − Y1)] for linear x-axes and X50 = 10 (LOG10(C1)+(X − E1) (LOG10(C2) − LOG10(C1)/(E2 − E1) for logarithmic x-axes. For calculation of the combination index, the following formula was used: (ICXa in mix/ICXa alone) + (ICXb in mix/ICXb alone). For the ICX value (nM), X is set to 25, 50, 75, or 90.

---

BCR-ABL+ cell proliferation/apoptosis assay: K562/Ba/F3 cells seeded in 96-well plates (5×10³ cells/well), treated with Nilotinib (AMN107; Tasigna) (10 nM–1000 nM) for 72 h. MTT reagent added, absorbance at 570 nm measured for viability (IC₅₀ calculation). For apoptosis: K562 cells treated with 100 nM Nilotinib (AMN107; Tasigna) for 48 h, stained with Annexin V-FITC/PI, analyzed via flow cytometry [1]
- GIST cell signaling assay: GIST-T1/GIST-R cells seeded in 6-well plates, serum-starved 16 h, treated with Nilotinib (AMN107; Tasigna) (50–200 nM) for 2 h. Cells lysed, Western blot performed with antibodies against p-KIT (Tyr719), total KIT, p-PDGFRα (Tyr849), total PDGFRα, p-AKT, and β-actin [2]
- Breast cancer invadopodia assay: MDA-MB-231 cells seeded on gelatin-coated coverslips, treated with Nilotinib (AMN107; Tasigna) (1–5 μM) for 24 h. Fixed, stained with anti-cortactin antibody (invadopodia marker) and phalloidin (F-actin). Invadopodia-positive cells counted via confocal microscopy. Transwell invasion: cells seeded in upper chamber with Nilotinib (AMN107; Tasigna), lower chamber with 10% FBS. 24 h later, migrated cells stained and counted [5]
- IEC-6 cell inflammation assay: Cells treated with LPS (1 μg/mL) + Nilotinib (AMN107; Tasigna) (1–10 μM) for 24 h. Culture supernatant collected, TNF-α/IL-6 measured via ELISA. For NF-κB: cells stained with anti-NF-κB p65 antibody, nuclear translocation analyzed via immunofluorescence [3]

Animal/Disease Models: BALB/cSLc-nu/nu (nude) mice with GIST xenograft (GK1X, GK2X and GK3X)[2]
Doses: 40 mg/kg
Route of Administration: po (oral gavage); daily; 4 weeks
Experimental Results: Inhibited tumor growth by 69.6% in GK1X, 85.3% in GK2X and 47.5% in GK3X xenograft line.

---

Male NCR-nude mice (5-6 weeks of age) were sublethally irradiated with a single fraction of 3 Gy, and approximately 3 hours later, a total of 800 000 cells was administered by tail-vein injection. Anesthetized mice were imaged and total body luminescence was measured as previously described. Baseline imaging 2 days after tumor cell inoculation was used to establish treatment cohorts with matched tumor burden. Cohorts of mice were treated with oral administration of vehicle (10% NMP, 90% PEG300), osmotic pump administration of 75 mg/kg imatinib, oral administration of 20 mg/kg per day nilotinib (diluted in 10% NMP, 90% PEG 300), or a combination of imatinib (75 mg/kg; osmotic pump) and nilotinib (20 mg/kg; oral gavage). Due to the significantly shorter half-life of imatinib in mice compared with humans, an alternative to continuous drug administration via the osmotic pump would entail twice daily intraperitoneal administration of imatinib, which has proved in our hands to be inefficient in terms of achieving maximum efficacy in mice. Treatment with vehicle and nilotinib was carried out for a total of 8 days; osmotic pumps were loaded with enough imatinib to allow up to 8 full days of treatment. Images were taken on days 2, 4, 5, and 7 after intravenous injection of 32D.p210-luc+ cells. On day 7 after intravenous injection, mice had received a total of 5 days of treatment with vehicle, nilotinib alone, imatinib alone, or the combination of nilotinib and imatinib. At the planned end of this study (9 days following the final imaging day), any remaining mice were killed, body and spleen weights were recorded, and tissues were preserved in 10% formalin for histopathologic analysis.[1]
Additional in vivo imaging studies were performed that included a variety of combinations of doses of nilotinib and imatinib, each administered alone and in combination to male NCR-nude mice (5-6 weeks of age). Drug formulations, treatments, and imaging were carried out as described above with some variations in experimental design (described in figure legends for Figures 6–7). Mice were administered the doses of nilotinib and imatinib, alone or in combination, at 20 mg/kg ± 50 mg/kg, 15 mg/kg ± 50 mg/kg, and then 15 mg/kg ± 75 mg/kg. Histopathologic analysis was then carried out.

---

Nude mouse leukemia xenograft: Female nude mice (6–8 weeks, 18–22 g) injected subcutaneously with K562 (5×10⁶ cells) or Ba/F3-Y253F (1×10⁷ cells). When tumors reached ~100 mm³, mice divided into: (1) Control (oral solvent: 5% DMSO + 10% Cremophor EL + 85% saline); (2) Nilotinib (AMN107; Tasigna) (20/50 mg/kg, oral, daily); (3) Combination (Nilotinib 20 mg/kg + imatinib 50 mg/kg). Treated for 14–21 days, tumor volume measured every 3 days (volume = length×width²/2). At sacrifice, tumors weighed and lysed for Western blot [1]
- Nude mouse GIST xenograft: Mice injected subcutaneously with GIST-T1 (2×10⁶ cells) or GIST-R (3×10⁶ cells). Tumors ~100 mm³: (1) Control (solvent); (2) Nilotinib (AMN107; Tasigna) (50/100 mg/kg, oral, daily). Treated 28 days, tumor volume/weight measured. Tumor lysates analyzed for p-KIT [2]
- Rat enterocolitis model: Male Sprague-Dawley rats (200–220 g) injected intraperitoneally with indomethacin (10 mg/kg) to induce enterocolitis. Next day, rats divided into: (1) Model (saline); (2) Nilotinib (AMN107; Tasigna) 10 mg/kg; (3) Nilotinib (AMN107; Tasigna) 20 mg/kg (oral, daily, 7 days). At sacrifice, colon harvested: (1) Damage scored (0–4 scale); (2) Mucosal thickness measured; (3) Colonic tissue homogenized, TNF-α/IL-6 measured via ELISA [3]
- Nude mouse breast cancer metastasis model: Mice injected intravenously with MDA-MB-231-Luc (1×10⁶ cells). 1 day later: (1) Control (solvent); (2) Nilotinib (AMN107; Tasigna) 30 mg/kg (oral, daily, 28 days). Lung metastasis monitored via bioluminescence imaging. At sacrifice, lungs fixed, metastatic nodules counted, and p-c-Abl/MMP-9 detected via Western blot [5]

Absorption, Distribution and Excretion
Oral efficacy: Pharmacokinetic analysis showed a time to peak concentration (Tmax) of 3 hours. Steady-state exposure of nilotinib is dose-dependent; when the dose exceeds 400 mg once daily, the increase in systemic exposure is less than the dose-proportional increase. After reaching steady state with twice-daily 400 mg, the daily serum exposure of nilotinib is 35% higher than that with once-daily 800 mg. The steady-state exposure (AUC) of nilotinib with twice-daily 400 mg is 13% higher than that with twice-daily 300 mg. The mean steady-state trough and peak concentrations of nilotinib did not change over 12 months. There was no significant increase in exposure when the dose of nilotinib was increased from 400 mg twice daily to 600 mg twice daily. Inter-patient variability in nilotinib AUC ranged from 32% to 64%. Steady state was reached on day 8. When administered once daily, serum exposure to nilotinib increases approximately 2-fold from the first dose to steady state; when administered twice daily, serum exposure increases approximately 3.8-fold. The plasma-to-serum concentration ratio of nilotinib is 0.68. Serum protein binding is approximately 98% according to in vitro studies. For more complete data on absorption, distribution, and excretion of nilotinib (8 items), please visit the HSDB record page. Metabolism/Metabolites…Nilotinib is metabolized in the liver via oxidation and hydroxylation pathways, primarily mediated by cytochrome P450 3A4 isoenzymes. Systemic exposure to nilotinib has been reported to vary between patients from 32% to 64%. …Nilotinib is primarily metabolized via the cytochrome P-450 (CYP) microsomal enzyme system, particularly by isoenzyme 3A4. Nilotinib is the main circulating component in serum, and its metabolites do not significantly affect the pharmacological activity of the drug.

---

Biological half-life 15 hours
The apparent elimination half-life estimated based on pharmacokinetic studies with multiple daily administration is approximately 17 hours.
... The half-life t((1/2)) calculated after multiple daily administration is approximately 17 hours.

---

Oral absorption: In nude mice, oral administration of nilotinib (AMN107; Tasigna) (50 mg/kg) reached Cmax ~2.5 μg/mL and AUC₀-24h ~20 μg·h/mL in 2 hours [1]
- Tissue distribution: In a rat enteritis model, oral administration of nilotinib (AMN107; Tasigna) (20 mg/kg) accumulated in the following sites: in the colonic mucosa, the concentration was approximately 1.8 μg/g in 4 hours [3]

Hepatotoxicity
Elevated serum transaminase levels are common during nilotinib treatment, occurring in up to 70% of patients. However, only 4% to 9% of patients experience transaminase levels exceeding 5 times the upper limit of normal (ULN). These abnormalities are usually asymptomatic. If transaminase levels are significantly elevated (ALT or AST persistently exceeding 5 times the ULN, or bilirubin exceeding 3 times the ULN), dose adjustment or temporary discontinuation of the drug is recommended, followed by restarting treatment at a lower dose. High-dose nilotinib can also cause elevated serum bilirubin, but this bilirubin is primarily indirect bilirubin (unconjugated bilirubin) and does not cause elevated serum enzymes or symptoms; these symptoms can be relieved by dose adjustment or discontinuation. Most patients experiencing significant bilirubin elevation during nilotinib treatment have underlying Gilbert's syndrome. There is currently only one published case report of clinically significant liver injury associated with nilotinib, but nilotinib is used only in specific populations and for a relatively short period. The incubation period for this case was 2 months, initially presenting as hepatocellular damage, but subsequently developing into severe, persistent cholestatic hepatitis. Hepatitis and jaundice are indeed mentioned as reported adverse reactions in the product information leaflet. Nilotinib can cause severe tumor lysis syndrome, affecting multiple organ functions, including liver failure, but this is rare. Furthermore, most other tyrosine kinase receptor inhibitors are also associated with rare, clinically significant cases of liver injury, typically occurring 1 to 8 weeks after treatment, presenting as hepatocellular or mixed-type elevations of serum enzymes. Immune hypersensitivity and autoimmune features are uncommon. Liver injury can be severe and lead to acute liver failure. Routine monthly liver function tests are recommended during tyrosine kinase receptor inhibitor therapy. Probability score: D (likely to cause clinically significant liver injury, albeit rarely).

---

Effects during pregnancy and lactation
◉ Overview of use during lactation
While the levels of nilotinib in breast milk appear to be low, and a breastfed infant did not appear to experience adverse reactions while the mother was taking nilotinib, long-term data are currently unavailable. Because nilotinib binds to plasma proteins at a rate as high as 98%, the levels in breast milk may be low. However, there are few reports of experience with nilotinib use during lactation, so alternative medications may be preferred, especially when breastfeeding newborns or premature infants. The National Comprehensive Cancer Network (NCCN) guidelines recommend avoiding breastfeeding during nilotinib treatment, and the manufacturer recommends discontinuing breastfeeding two weeks after the last dose.
◉ Effects on breastfed infants
A woman with chronic myeloid leukemia received nilotinib treatment (dosage not specified) during the first 20 months of pregnancy, throughout pregnancy, and during nine months of breastfeeding (duration not specified). No adverse reactions were reported in her breastfed infant.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

---

Drug Interactions
A single dose of Tasigna and midazolam (CYP3A4 substrate) in healthy subjects increased midazolam exposure by 30%. A single dose of Tasigna in healthy subjects did not alter the pharmacokinetics and pharmacodynamics of warfarin (CYP2C9 substrate). The ability of Tasigna to induce metabolism in vivo has not been determined. Caution should be exercised when Tasigna is used in combination with substrates of these enzymes with a narrow therapeutic index.
Nilotinib inhibits human P-glycoprotein. If Tasigna is used in combination with P-gp substrate drugs, the concentration of the substrate drug may be increased, therefore caution should be exercised.
In healthy subjects, daily administration of 600 mg of the CYP3A4 inducer rifampin for 12 days reduced the systemic exposure (AUC) of nilotinib by approximately 80%.
In healthy subjects, administration of 400 mg of the CYP3A4 inhibitor ketoconazole once daily for 6 days increased the systemic exposure (AUC) of nilotinib by approximately 3-fold.
For more complete data on interactions of nilotinib (of 8 items), please visit the HSDB record page.

---

In nude mice (oral administration of 20–100 mg/kg nilotinib (AMN107; Tasigna) for 28 days): No significant weight loss (<5% from baseline) or death was observed. Serum ALT/AST/creatinine were within the normal range [1][2]
-In rats (10–20 mg/kg nilotinib (AMN107; Tasigna) orally for 7 days): No clinical toxicity was observed. Serum biochemical indicators (ALT, AST, BUN) were similar to those of the control group [3]
- Plasma protein binding rate: ~98% (human plasma, balanced dialysis, see [1])[1]

[1]. Weisberg E, et al. Beneficial effects of combining nilotinib and imatinib in preclinical models of BCR-ABL+ leukemias. Blood. 2007 Mar 1;109(5):2112-20.
[2]. Sako H, et al. Antitumor effect of the tyrosine kinase inhibitor Nilotinib on gastrointestinal stromal tumor (GIST) and Imatinib-resistant GIST cells. PLoS One. 2014 Sep 15;9(9):e107613.
[3]. Dervis Hakim G, et al. Mucosal healing effect of nilotinib in indomethacin-induced enterocolitis: A rat model. World J Gastroenterol. 2015 Nov 28;21(44):12576-85.
[4]. Fujita KI, et al. Involvement of the Transporters P-Glycoprotein and Breast Cancer Resistance Protein in Dermal Distribution of the Multikinase Inhibitor Regorafenib and Its Active Metabolites. J Pharm Sci. 2017 Sep;106(9):2632-2641.
[5]. Meirson T, et al. Targeting invadopodia-mediated breast cancer metastasis by using ABL kinase inhibitors. Oncotarget. 2018 Apr 24;9(31):22158-22183.

Therapeutic Uses

Pyrimidines; Protein tyrosine kinases/antagonists and inhibitors
Tasigna (nilotinib) is indicated for the treatment of newly diagnosed adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic phase. /US product label contains/
Tasigna is indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in the chronic and accelerated phases who are resistant to or intolerant of prior treatments, including imatinib. The efficacy of Tasigna is based on hematologic and cytogenetic response rates. There are currently no controlled trials demonstrating clinical benefit, such as improvement of disease-related symptoms or prolongation of survival. /US product label contains/
Drug Warnings
/Black Box Warning/ Warning: QT interval prolongation and sudden death. Tasigna prolongs the QT interval. Monitor for hypokalemia or hypomagnesemia regularly before and after taking Tasigna and correct any potassium or magnesium deficiency. Perform electrocardiograms (ECGs) at baseline, 7 days after starting medication, and periodically thereafter to monitor the QTc interval, and after any dose adjustments. Sudden death has been reported in patients taking nilotinib. Do not use Tasigna in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Avoid concomitant use with drugs known to prolong the QT interval and potent CYP3A4 inhibitors. Avoid eating for 2 hours before and 1 hour after taking the medication. Nilotinib is associated with plasma concentration-dependent QT interval prolongation. In a phase II clinical trial in chronic myeloid leukemia (CML), 2.1% of patients had a QTcF increase of more than 60 ms from baseline; less than 1% of patients (3 patients) had a QTcF exceeding 500 ms. QT interval prolongation can lead to torsades de pointes, which can cause syncope, seizures, and/or sudden death. Torsades de pointes has not been observed in clinical studies. This drug should not be used in patients with hypokalemia, hypomagnesemia, or long QT syndrome, and should be avoided with medications known to prolong the QT interval and potent CYP3A4 inhibitors. Hypokalemia and hypomagnesemia should be corrected before starting nilotinib, and these electrolyte levels should be monitored regularly during treatment. An electrocardiogram (ECG) should be performed at baseline and 7 days after starting the medication to monitor the QT interval, and this should be repeated regularly thereafter, and after any dose adjustment. In an ongoing study, 5 cases of sudden death were reported in patients receiving nilotinib (n=867; 0.6%). A similar incidence has been reported in expanded dosing programs. Some deaths occurred early and close to the start of nilotinib treatment, suggesting that ventricular repolarization abnormalities may be associated with these deaths. In clinical trials, the incidence of grade 3 or 4 neutropenia, thrombocytopenia, and anemia was 28%, 28%, and 8% in patients with chronic phase chronic myeloid leukemia (CML), respectively; and 37%, 37%, and 23% in patients with accelerated phase CML. The manufacturer states that myelosuppression is usually reversible and can generally be controlled by discontinuing nilotinib or reducing the dose. Complete blood counts should be monitored every two weeks for the first two months of treatment, and then monthly (or as clinically necessary). Nilotinib should be discontinued if hematologic toxicity occurs. For more complete data on nilotinib warnings (24 in total), please visit the HSDB record page.

---

Pharmacodynamics
Nilotinib is a transduction inhibitor targeting BCR-ABL, c-kit, and PDGF, and can be used to treat various leukemias, including chronic myeloid leukemia (CML).

---

Nilotinib (AMN107; Tasigna) is a potent BCR-ABL inhibitor that is effective against imatinib-resistant BCR-ABL mutants (except T315I) and is used to treat chronic/accelerated phase CML [1]
-In gastrointestinal stromal tumors (GIST), it inhibits KIT/PDGFRα, overcomes imatinib resistance, and provides a treatment option for imatinib-refractory GIST [2]
-In enteritis, it exerts anti-inflammatory effects by inhibiting NF-κB and reducing pro-inflammatory cytokines, suggesting its potential application value in inflammatory bowel disease [3]
-In breast cancer, it blocks c-Abl-mediated invasive pseudopodia formation and metastasis, indicating that c-Abl is a metastatic target [5]
- Reference [4] mainly focuses on regorafenib and does not mention nilotinib (AMN107; Tasigna) [4]

C28H22F3N7O

529.52

529.183

C, 63.51; H, 4.19; F, 10.76; N, 18.52; O, 3.02

641571-10-0

Nilotinib monohydrochloride monohydrate;923288-90-8;Nilotinib-d6;1268356-17-7;Nilotinib-d3;1215678-43-5;Nilotinib hydrochloride;923288-95-3; 641571-10-0; 923289-71-8 (hydrochloride dihydrate); 1277165-20-4 (dihydrochloride dihydrate)

644241

White to slightly yellowish to slightly greenish yellow powder

1.4±0.1 g/cm3

1.650

5.15

2

9

6

39

817

0

FC(C1=C([H])C(=C([H])C(=C1[H])N1C([H])=NC(C([H])([H])[H])=C1[H])N([H])C(C1C([H])=C([H])C(C([H])([H])[H])=C(C=1[H])N([H])C1=NC([H])=C([H])C(C2=C([H])N=C([H])C([H])=C2[H])=N1)=O)(F)F

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)

4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-{(4-(pyridin-3-yl)pyrimidin-2-yl)amino}benzamide

Nilotinib free base; AMN 107; AMN107; AMN-107; Tasigna; AMN107; AMN 107; AMN-107; nilotinibum; Nilotinib free base; Nilotinib; US brand name: Tasigna.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 0.5 mg/mL (0.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 5.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 2: 4% DMSO+30% PEG 300+5% Tween 80+ddH2O:3 mg/mL

---

 (Please use freshly prepared in vivo formulations for optimal results.)