Nilotinib HCl hydrate
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MedKoo CAT#: 100673

CAS#: 923288-90-8 (HCl hydrate)

Description: Nilotinib, also known as AMN-107, is an orally bioavailable aminopyrimidine-derivative Bcr-Abl tyrosine kinase inhibitor with antineoplastic activity. Designed to overcome imatinib resistance, nilotinib binds to and stabilizes the inactive conformation of the kinase domain of the Abl protein of the Bcr-Abl fusion protein, resulting in the inhibition of the Bcr-Abl-mediated proliferation of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) cells. This agent also inhibits the receptor tyrosine kinases platelet-derived growth factor receptor (PDGF-R) and c-kit, a receptor tyrosine kinase mutated and constitutively activated in most gastrointestinal stromal tumors (GISTs).


Chemical Structure

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Nilotinib HCl hydrate
CAS# 923288-90-8 (HCl hydrate)

Theoretical Analysis

MedKoo Cat#: 100673
Name: Nilotinib HCl hydrate
CAS#: 923288-90-8 (HCl hydrate)
Chemical Formula: C28H25ClF3N7O2
Exact Mass: 529.1838
Molecular Weight: 584.0
Elemental Analysis: C, 57.59; H, 4.32; Cl, 6.07; F, 9.76; N, 16.79; O, 5.48

Price and Availability

Size Price Availability Quantity
1.0g USD 250.0 Same Day
2.0g USD 450.0 Same Day
5.0g USD 850.0 Same Day
10.0g USD 1250.0 Same Day
20.0g USD 2150.0 Same Day
50.0g USD 3650.0 Same Day
100.0g USD 4850.0 2 Weeks
200.0g USD 5950.0 2 Weeks
500.0g USD 7450.0 2 Weeks
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Related CAS #: 923288-90-8 (HCl hydrate)   923288-95-3(HCl)   641571-10-0 (free base)    

Synonym: AMN 107; AMN107; AMN-107; Nilotinib; US brand name: Tasigna. Nilotinib HCl hydrate.

IUPAC/Chemical Name: 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate

InChi Key: YCBPQSYLYYBPDW-UHFFFAOYSA-N

InChi Code: InChI=1S/C28H22F3N7O.ClH.H2O/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;1H2

SMILES Code: O=C(NC1=CC(C(F)(F)F)=CC(N2C=C(C)N=C2)=C1)C3=CC=C(C)C(NC4=NC=CC(C5=CC=CN=C5)=N4)=C3.[H]Cl.[H]O[H]

Appearance: White to off-white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Nilotinib monohydrochloride monohydrate is a second generation tyrosine kinase inhibitor (TKI), is significantly potent against BCRABL, and is active against many BCR-ABL mutants.
In vitro activity: Abl kinase inhibitors were previously reported to exert inhibitory activities against different viruses, including SARS‐CoV and MERS‐CoV by blocking the fusion between viral envelope and endosomal membrane. 4 , 5 , 6 Therefore, at first, we tested three Abl kinase inhibitors, namely nilotinib, imatinib and dasatinib, at non‐toxic concentration in Vero‐E6 cells by treating the cells starting 1h before infection. The only compound showing inhibitory activity is nilotinib with an EC50 of 1.88 µM (Table 1). Subsequently, nilotinib was also tested by only adding the compound 1h after inoculation. Nilotinib showed a comparable inhibitory activity in this condition, with an EC50 of 1.44 µM. In conclusion, although preliminary, the results of this in vitro study demonstrate the promising antiviral activity of nilotinib, a Bcr‐Abl tyrosine kinase inhibitor, not previously investigated to combat SARSCoV‐2. Basic Clin Pharmacol Toxicol. 2020 Dec 4 : 10.1111/bcpt.13537. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753569/
In vivo activity: Mice were infected with pathogenic M. bovis and after one week of infection, nilotinib was injected at a dose rate of 5 mg/kg and 10 mg/kg on alternate days. The dose of nilotinib used in the current study for in-vivo experiments was under a clinically relevant dose as previously reported. Animals were slaughtered at various time points after infection (Figure 6A). The total body weight of animals and their lung and spleen weights revealed that nilotinib suppressed the degree of pathogenesis of M. bovis (Supplementary Figure S5B– D). Gross analysis showed that nilotinib reduced the development of lesions in the lungs of infected mice as compared to the untreated control group (Figure 6B). At an early stage of infection (35 dpi), there was no significant difference in the spleen size, while in the later stages untreated mice (images labeled with II) showed enlarged spleens compared to those in the treated infected mice (images labeled with III and IV) (Figure 6C). Furthermore, the lung lobe showed a significantly high% area covered by lesions in untreated mice compared to treated M. bovis infected mice at all time points (Figure 6D,E). In addition, the increased number of bacilli was observed in the lung sections of untreated animals in comparison to treated animals after staining with the Ziehl-Neelsen staining method (Supplementary Figure S5E). Next, the harvested lung and spleen tissues were subjected to histopathological analyses. At early stages of infection (35 dpi), treated mice had small foci of inflammation composed of epithelioid macrophages and lymphocytes with no clear evidence of necrosis (Data not shown). However, at a later stage of infection (63 dpi), at high magnification, granulomatous lesions from untreated animals showed necrotic areas (marked with red arrows) in the central region of the lesion, which represent the severity of the disease (Figure 6F). Interestingly, lung sections from nilotinib treated animals showed comparatively less severe lesions with a reduced necrotic core (Figure 6G,H). Notably, no histological changes were observed in the H&E stained sections of the livers and the kidneys of nilotinib treated mice compared to the untreated controls (Supplemental Figure S4A,B). These findings suggested that nilotinib contributed towards minimizing the severity of M. bovis pathogenesis in mice. Cells. 2019 May; 8(5): 506. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562972/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 33.0 56.5

Preparing Stock Solutions

The following data is based on the product molecular weight 584.0 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Hussain T, Zhao D, Shah SZA, Sabir N, Wang J, Liao Y, Song Y, Dong H, Hussain Mangi M, Ni J, Yang L, Zhou X. Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy. Cells. 2019 May 26;8(5):506. doi: 10.3390/cells8050506. PMID: 31130711; PMCID: PMC6562972. 2. Cagno V, Magliocco G, Tapparel C, Daali Y. The tyrosine kinase inhibitor nilotinib inhibits SARS-CoV-2 in vitro. Basic Clin Pharmacol Toxicol. 2021 Apr;128(4):621-624. doi: 10.1111/bcpt.13537. Epub 2020 Dec 4. PMID: 33232578; PMCID: PMC7753569. 3. Hussain T, Zhao D, Shah SZA, Sabir N, Wang J, Liao Y, Song Y, Dong H, Hussain Mangi M, Ni J, Yang L, Zhou X. Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy. Cells. 2019 May 26;8(5):506. doi: 10.3390/cells8050506. PMID: 31130711; PMCID: PMC6562972 4. Chahal KK, Li J, Kufareva I, Parle M, Durden DL, Wechsler-Reya RJ, Chen CC, Abagyan R. Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma. PLoS One. 2019 Sep 20;14(9):e0214901. doi: 10.1371/journal.pone.0214901. PMID: 31539380; PMCID: PMC6754133.
In vitro protocol: 1. Hussain T, Zhao D, Shah SZA, Sabir N, Wang J, Liao Y, Song Y, Dong H, Hussain Mangi M, Ni J, Yang L, Zhou X. Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy. Cells. 2019 May 26;8(5):506. doi: 10.3390/cells8050506. PMID: 31130711; PMCID: PMC6562972. 2. Cagno V, Magliocco G, Tapparel C, Daali Y. The tyrosine kinase inhibitor nilotinib inhibits SARS-CoV-2 in vitro. Basic Clin Pharmacol Toxicol. 2021 Apr;128(4):621-624. doi: 10.1111/bcpt.13537. Epub 2020 Dec 4. PMID: 33232578; PMCID: PMC7753569.
In vivo protocol: 1. Hussain T, Zhao D, Shah SZA, Sabir N, Wang J, Liao Y, Song Y, Dong H, Hussain Mangi M, Ni J, Yang L, Zhou X. Nilotinib: A Tyrosine Kinase Inhibitor Mediates Resistance to Intracellular Mycobacterium Via Regulating Autophagy. Cells. 2019 May 26;8(5):506. doi: 10.3390/cells8050506. PMID: 31130711; PMCID: PMC6562972. 2. Chahal KK, Li J, Kufareva I, Parle M, Durden DL, Wechsler-Reya RJ, Chen CC, Abagyan R. Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma. PLoS One. 2019 Sep 20;14(9):e0214901. doi: 10.1371/journal.pone.0214901. PMID: 31539380; PMCID: PMC6754133.

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1. Kuo YC, Tsai HC, Rajesh R. Glutathione Liposomes Carrying Ceftriaxone, FK506, and Nilotinib to Control Overexpressed Dopamine Markers and Apoptotic Factors in Neurons. ACS Biomater Sci Eng. 2021 Jul 12;7(7):3242-3255. doi: 10.1021/acsbiomaterials.1c00555. Epub 2021 Jun 30. PMID: 34189904.

1: Breccia M, Arboscello E, Bellodi A, Colafigli G, Molica M, Bergamaschi M, Massaro F, Quattrocchi L, Sarocchi M, Spallarossa P, Alimena G. Proposal for a tailored stratification at baseline and monitoring of cardiovascular effects during follow-up in chronic phase chronic myeloid leukemia patients treated with nilotinib frontline. Crit Rev Oncol Hematol. 2016 Nov;107:190-198. doi: 10.1016/j.critrevonc.2016.10.002. Review. PubMed PMID: 27823647.

2: Fujimi A, Sakamoto H, Kanisawa Y, Minami S, Nagamachi Y, Yamauchi N, Ibata S, Kato J. Pneumatosis intestinalis during chemotherapy with nilotinib in a patient with chronic myeloid leukemia who tested positive for anti-topoisomerase I antibodies. Clin J Gastroenterol. 2016 Dec;9(6):358-364. Review. PubMed PMID: 27638345.

3: Emole J, Talabi T, Pinilla-Ibarz J. Update on the management of Philadelphia chromosome positive chronic myelogenous leukemia: role of nilotinib. Biologics. 2016 Feb 26;10:23-31. doi: 10.2147/BTT.S67844. Review. PubMed PMID: 27013862; PubMed Central PMCID: PMC4777272.

4: Sekiguchi Y, Shimada A, Matsuzawa M, Imai H, Wakabayashi M, Sugimoto K, Nakamura N, Sawada T, Arita J, Komatsu N, Noguchi M. Occurrence of Carcinoma of the Pancreas Following Nilotinib Therapy for Chronic Myeloid Leukemia: Report of a Case with Review of the Literature. Turk J Haematol. 2015 Sep;32(3):257-62. doi: 10.4274/tjh.2013.0322. Review. PubMed PMID: 26376592; PubMed Central PMCID: PMC4563202.

5: Miura M. Therapeutic drug monitoring of imatinib, nilotinib, and dasatinib for patients with chronic myeloid leukemia. Biol Pharm Bull. 2015;38(5):645-54. doi: 10.1248/bpb.b15-00103. Review. PubMed PMID: 25947908.

6: Kaur S, Arora AK, Sekhon JS, Sood N. Nilotinib-induced psoriasis in a patient of chronic myeloid leukemia responding to methotrexate. Indian J Dermatol Venereol Leprol. 2015 Mar-Apr;81(2):216-8. doi: 10.4103/0378-6323.152311. Review. PubMed PMID: 25751356.

7: Weisberg E, Nonami A, Griffin JD. Combination therapy with nilotinib for drug-sensitive and drug-resistant BCR-ABL-positive leukemia and other malignancies. Arch Toxicol. 2014 Dec;88(12):2233-42. doi: 10.1007/s00204-014-1385-5. Review. PubMed PMID: 25331939.

8: Ostendorf BN, le Coutre P, Kim TD, Quintás-Cardama A. Nilotinib. Recent Results Cancer Res. 2014;201:67-80. doi: 10.1007/978-3-642-54490-3_3. Review. PubMed PMID: 24756785.

9: Capuozzo M, Ottaiano A, Nava E, Cascone S, Cinque C, Vercellone A, Scognamiglio C, Palumbo E, Iaffaioli RV. Nilotinib for the Frontline Treatment of Chronic Myeloid Leukemia Carrying the p230 Transcript: Dream or Reality? Front Oncol. 2014 Feb 3;4:17. doi: 10.3389/fonc.2014.00017. Review. PubMed PMID: 24551597; PubMed Central PMCID: PMC3910244.

10: Signorovitch J, Ayyagari R, Reichmann WM, Wu EQ, Chen L. Major molecular response during the first year of dasatinib, imatinib or nilotinib treatment for newly diagnosed chronic myeloid leukemia: a network meta-analysis. Cancer Treat Rev. 2014 Mar;40(2):285-92. doi: 10.1016/j.ctrv.2013.09.004. Review. PubMed PMID: 24112812.

11: Eadie LN, Hughes TP, White DL. Interaction of the efflux transporters ABCB1 and ABCG2 with imatinib, nilotinib, and dasatinib. Clin Pharmacol Ther. 2014 Mar;95(3):294-306. doi: 10.1038/clpt.2013.208. Review. PubMed PMID: 24107928.

12: Kanda T, Ishikawa T, Takahashi T, Nishida T. Nilotinib for treatment of gastrointestinal stromal tumors: out of the equation? Expert Opin Pharmacother. 2013 Sep;14(13):1859-67. doi: 10.1517/14656566.2013.816676. Review. PubMed PMID: 23834614.

13: Brazzelli V, Grasso V, Borroni G. Imatinib, dasatinib and nilotinib: a review of adverse cutaneous reactions with emphasis on our clinical experience. J Eur Acad Dermatol Venereol. 2013 Dec;27(12):1471-80. doi: 10.1111/jdv.12172. Review. PubMed PMID: 23611501.

14: Quintás-Cardama A, Jabbour EJ. Considerations for early switch to nilotinib or dasatinib in patients with chronic myeloid leukemia with inadequate response to first-line imatinib. Leuk Res. 2013 May;37(5):487-95. doi: 10.1016/j.leukres.2013.01.006. Review. PubMed PMID: 23391518.

15: Deadman BJ, Hopkin MD, Baxendale IR, Ley SV. The synthesis of Bcr-Abl inhibiting anticancer pharmaceutical agents imatinib, nilotinib and dasatinib. Org Biomol Chem. 2013 Mar 21;11(11):1766-800. doi: 10.1039/c2ob27003j. Review. PubMed PMID: 23247657.

16: Drucker AM, Wu S, Busam KJ, Berman E, Amitay-Laish I, Lacouture ME. Rash with the multitargeted kinase inhibitors nilotinib and dasatinib: meta-analysis and clinical characterization. Eur J Haematol. 2013 Feb;90(2):142-50. doi: 10.1111/ejh.12052. Review. PubMed PMID: 23240881.

17: Pavey T, Hoyle M, Ciani O, Crathorne L, Jones-Hughes T, Cooper C, Osipenko L, Venkatachalam M, Rudin C, Ukoumunne O, Garside R, Anderson R. Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia: systematic reviews and economic analyses. Health Technol Assess. 2012;16(42):iii-iv, 1-277. doi: 10.3310/hta16420. Review. PubMed PMID: 23134589.

18: Loveman E, Cooper K, Bryant J, Colquitt JL, Frampton GK, Clegg A. Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess. 2012;16(23):iii-xiii, 1-137. doi: 10.3310/hta16230. Review. PubMed PMID: 22564553; PubMed Central PMCID: PMC4781455.

19: Rogers G, Hoyle M, Thompson Coon J, Moxham T, Liu Z, Pitt M, Stein K. Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid leukaemia: a systematic review and economic evaluation. Health Technol Assess. 2012;16(22):1-410. doi: 10.3310/hta16220. Review. PubMed PMID: 22551803; PubMed Central PMCID: PMC4781389.

20: Tran A, Tawbi HA. A potential role for nilotinib in KIT-mutated melanoma. Expert Opin Investig Drugs. 2012 Jun;21(6):861-9. doi: 10.1517/13543784.2012.679341. Review. PubMed PMID: 22500535.



Additional Information

 
Nilotinib was approved as Tasigna in the USA and the EU for drug-resistant chronic myelogenous leukemia (CML). In June 2006, a Phase I clinical trial found nilotinib, also known by its clinical code AMN107, has a relatively favorable safety profile and shows activity in cases of CML resistant to treatment with imatinib (Gleevec), another tyrosine kinase inhibitor currently used as a first-line treatment. In that study 92% of patients (already resistant or unresponsive to Gleevec) achieved a normal white blood cell counts after five months of treatment. The drug carries a black box warning for possible heart complications.
 
Tasigna (nilotinib) belongs to a pharmacologic class of drugs known as kinase inhibitors. Nilotinib drug substance, a monohydrate mono-hydrochloride, is a white to slightly yellowish to slightly greenish yellow powder with the anhydrous molecular formula and weight, respectively, of C28H22F3N7O•HCl • H2O and 565.98. The solubility of nilotinib in aqueous solutions decreases with increasing pH. Nilotinib is not optically active. The pKa1 was determined to be 2.1; pKa2 was estimated to be 5.4. The chemical name of nilotinib is 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide, monohydrochloride, monohydrate.  Tasigna (nilotinib) capsules, for oral use, contain 200 mg nilotinib base, anhydrous (as hydrochloride, monohydrate) with the following inactive ingredients: colloidal silicon dioxide, crospovidone, lactose monohydrate, magnesium stearate and polyoxamer 188. The capsules contain gelatin, iron oxide (red), iron oxide (yellow), and titanium dioxide.
 
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), c-Kit (210 nM), CSR-1R (125-250 nM) and DDR (3.7 nM).