Brigatinib (AP-26113)
featured

    WARNING: This product is for research use only, not for human or veterinary use.

MedKoo CAT#: 206488

CAS#: 1197953-54-0

Description: Brigatinib, also known as AP-26113, is an orally active, potent and selective Dual ALK/EGFR inhibitor. AP26113 binds to and inhibits ALK kinase and ALK fusion proteins as well as EGFR and mutant forms. This leads to the inhibition of ALK kinase and EGFR kinase, disrupts their signaling pathways and eventually inhibits tumor cell growth in susceptible tumor cells. In addition, AP26113 appears to overcome mutation-based resistance. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development; ALK dysregulation and gene rearrangements are associated with a series of tumors. EGFR is overexpressed in a variety of cancer cell types.


Chemical Structure

img
Brigatinib (AP-26113)
CAS# 1197953-54-0

Theoretical Analysis

MedKoo Cat#: 206488
Name: Brigatinib (AP-26113)
CAS#: 1197953-54-0
Chemical Formula: C29H39ClN7O2P
Exact Mass: 583.25914
Molecular Weight: 584.10176
Elemental Analysis: C, 59.63; H, 6.73; Cl, 6.07; N, 16.79; O, 5.48; P, 5.30

Price and Availability

Size Price Availability Quantity
100.0mg USD 150.0 Ready to ship
200.0mg USD 250.0 Ready to ship
500.0mg USD 550.0 Ready to ship
1.0g USD 850.0 Ready to ship
2.0g USD 1450.0 Ready to ship
5.0g USD 2150.0 Ready to ship
10.0g USD 3650.0 Ready to ship
20.0g USD 4650.0 2 Weeks
50.0g USD 8650.0 2 Weeks
Click to view more sizes and prices
Bulk inquiry

Related CAS #: 1197958-12-5 (analog)   1197953-54-0    

Synonym: AP26113; AP-26113; AP 26113, Brigatinib; Alunbrig.

IUPAC/Chemical Name: (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

InChi Key: AILRADAXUVEEIR-UHFFFAOYSA-N

InChi Code: InChI=1S/C29H39ClN7O2P/c1-35-15-17-37(18-16-35)21-11-13-36(14-12-21)22-9-10-24(26(19-22)39-2)33-29-31-20-23(30)28(34-29)32-25-7-5-6-8-27(25)40(3,4)38/h5-10,19-21H,11-18H2,1-4H3,(H2,31,32,33,34)

SMILES Code: CN1CCN(C2CCN(C3=CC=C(NC4=NC=C(Cl)C(NC5=CC=CC=C5P(C)(C)=O)=N4)C(OC)=C3)CC2)CC1

Appearance: Light yellow 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 (2 mg /mL) or ethanol (10mg/mL)

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: Brigatinib (AP-26113) is a highly potent and selective ALK inhibitor, with an IC50 of 0.6 nM.
In vitro activity: The activity of brigatinib against native ALK and a number of non-ALK kinases was next examined in cellular assays (Table 1). Consistent with in vitro kinase data, brigatinib inhibited ALK and ROS1 with similar potencies (IC50, 14 and 18 nmol/L, respectively). Compared with ALK, brigatinib inhibited FLT3 and IGF-1R with about 11-fold lower potency (IC50, 148–158 nmol/L) and inhibited mutant variants of FLT3 and EGFR with 15- to 35-fold lower potency (IC50, 211–489 nmol/L), despite inhibiting some of these kinases (e.g., FLT3, FLT3 [D835Y], and EGFR [L858R]) with potency similar to ALK in in vitro kinase assays. Finally, brigatinib lacked cellular activity against INSR and native EGFR (IC50 > 3,000 nmol/L). Overall, these results suggest that brigatinib is a highly potent and selective ALK and ROS1 inhibitor.In a panel of seven ALCL and NSCLC cell lines that express NPM-ALK or EML4-ALK fusions, the concentration of brigatinib that inhibited growth by 50% (GI50) ranged from 4 to 31 nmol/L, and the concentration that inhibited ALK phosphorylation by 50% (IC50) ranged from 1.5 to 12 nmol/L (Fig. 2A and B). Potent inhibition of downstream signaling was also observed in both ALCL and NSCLC cell lines (Supplementary Fig. S5). Across three ALK-negative ALCL and NSCLC cell lines, the GI50 values for brigatinib ranged from 503 to 2,387 nmol/L. Thus, overall, brigatinib potently inhibited ALK activity and proliferation in all ALK+ cell lines tested and exhibited more than 100-fold selectivity over ALK-negative lines. Reference: Clin Cancer Res. 2016 Nov 15;22(22):5527-5538. https://clincancerres.aacrjournals.org/content/22/22/5527.long
In vivo activity: The in vivo activity of brigatinib was examined in ALK+ Karpas-299 (ALCL) and H2228 (NSCLC) xenograft mouse models, with oral administration of brigatinib (10, 25, or 50 mg/kg once daily) leading to a dose-dependent inhibition of tumor growth in both models. In the Karpas-299 model, 25 mg/kg inhibited tumor growth by 87% and 50 mg/kg induced near complete tumor regression that was maintained for at least 13 days after treatment (Fig. 2C). Increased efficacy was associated with increased plasma levels of brigatinib and deeper and more sustained inhibition of ALK signaling in the tumor (Supplementary Fig. S6A and S6B). H2228-derived tumors, possibly because of their slower growth rate, were even more sensitive to ALK inhibition than Karpas-299–derived tumors, with 10, 25, or 50 mg/kg brigatinib inducing substantial tumor regression that was maintained for more than 28 days after treatment (Fig. 2C). Reference: Clin Cancer Res. 2016 Nov 15;22(22):5527-5538. https://clincancerres.aacrjournals.org/content/22/22/5527.long

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 3.0 5.14
Ethanol 10.0 17.12

Preparing Stock Solutions

The following data is based on the product molecular weight 584.10176 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. Zhang S, Anjum R, Squillace R, Nadworny S, Zhou T, Keats J, Ning Y, Wardwell SD, Miller D, Song Y, Eichinger L, Moran L, Huang WS, Liu S, Zou D, Wang Y, Mohemmad Q, Jang HG, Ye E, Narasimhan N, Wang F, Miret J, Zhu X, Clackson T, Dalgarno D, Shakespeare WC, Rivera VM. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res. 2016 Nov 15;22(22):5527-5538. doi: 10.1158/1078-0432.CCR-16-0569. Epub 2016 Oct 25. PMID: 27780853. 2. Siaw JT, Wan H, Pfeifer K, Rivera VM, Guan J, Palmer RH, Hallberg B. Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice. Oncotarget. 2016 May 17;7(20):29011-22. doi: 10.18632/oncotarget.8508. PMID: 27049722; PMCID: PMC5045374.
In vitro protocol: 1. Zhang S, Anjum R, Squillace R, Nadworny S, Zhou T, Keats J, Ning Y, Wardwell SD, Miller D, Song Y, Eichinger L, Moran L, Huang WS, Liu S, Zou D, Wang Y, Mohemmad Q, Jang HG, Ye E, Narasimhan N, Wang F, Miret J, Zhu X, Clackson T, Dalgarno D, Shakespeare WC, Rivera VM. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res. 2016 Nov 15;22(22):5527-5538. doi: 10.1158/1078-0432.CCR-16-0569. Epub 2016 Oct 25. PMID: 27780853. 2. Siaw JT, Wan H, Pfeifer K, Rivera VM, Guan J, Palmer RH, Hallberg B. Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice. Oncotarget. 2016 May 17;7(20):29011-22. doi: 10.18632/oncotarget.8508. PMID: 27049722; PMCID: PMC5045374.
In vivo protocol: 1. Zhang S, Anjum R, Squillace R, Nadworny S, Zhou T, Keats J, Ning Y, Wardwell SD, Miller D, Song Y, Eichinger L, Moran L, Huang WS, Liu S, Zou D, Wang Y, Mohemmad Q, Jang HG, Ye E, Narasimhan N, Wang F, Miret J, Zhu X, Clackson T, Dalgarno D, Shakespeare WC, Rivera VM. The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models. Clin Cancer Res. 2016 Nov 15;22(22):5527-5538. doi: 10.1158/1078-0432.CCR-16-0569. Epub 2016 Oct 25. PMID: 27780853. 2. Siaw JT, Wan H, Pfeifer K, Rivera VM, Guan J, Palmer RH, Hallberg B. Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK-positive neuroblastoma cells, Drosophila and mice. Oncotarget. 2016 May 17;7(20):29011-22. doi: 10.18632/oncotarget.8508. PMID: 27049722; PMCID: PMC5045374.

Molarity Calculator

Calculate the mass, volume, or concentration required for a solution.
=
x
x
g/mol

*When preparing stock solutions always use the batch-specific molecular weight of the product found on the vial label and SDS / CoA (available online).

Reconstitution Calculator

The reconstitution calculator allows you to quickly calculate the volume of a reagent to reconstitute your vial. Simply enter the mass of reagent and the target concentration and the calculator will determine the rest.

=
÷

Dilution Calculator

Calculate the dilution required to prepare a stock solution.
x
=
x

1: Huber RM, Hansen KH, Paz-Ares Rodríguez L, West HL, Reckamp KL, Leighl NB, Tiseo M, Smit EF, Kim DW, Gettinger SN, Hochmair MJ, Kim SW, Langer CJ, Ahn MJ, Kim ES, Kerstein D, Groen HJM, Camidge DR. Brigatinib in Crizotinib-Refractory ALK+ Non-Small Cell Lung Cancer: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial. J Thorac Oncol. 2019 Nov 19. pii: S1556-0864(19)33645-7. doi: 10.1016/j.jtho.2019.11.004. [Epub ahead of print] PubMed PMID: 31756496.

2: Sharma GG, Cortinovis D, Agustoni F, Arosio G, Villa M, Cordani N, Bidoli P, Bisson WH, Pagni F, Piazza R, Gambacorti-Passerini C, Mologni L. A Compound L1196M/G1202R ALK Mutation in a Patient with ALK-Positive Lung Cancer with Acquired Resistance to Brigatinib Also Confers Primary Resistance to Lorlatinib. J Thorac Oncol. 2019 Nov;14(11):e257-e259. doi: 10.1016/j.jtho.2019.06.028. PubMed PMID: 31668326.

3: Monzonís X, Arriola E. Early Onset Pulmonary Toxicity With Lorlatinib in a Patient With Previous Pulmonary Toxicity From Brigatinib. J Thorac Oncol. 2019 Nov;14(11):e247-e248. doi: 10.1016/j.jtho.2019.06.013. PubMed PMID: 31668321.

4: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Available from http://www.ncbi.nlm.nih.gov/books/NBK548523/ PubMed PMID: 31643841.

5: Descourt R, Perol M, Rousseau-Bussac G, Planchard D, Mennecier B, Wislez M, Cortot A, Guisier F, Galland L, Dô P, Schott R, Dansin E, Arrondeau J, Auliac JB, Chouaid C. Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study). Lung Cancer. 2019 Oct;136:109-114. doi: 10.1016/j.lungcan.2019.08.010. Epub 2019 Aug 14. PubMed PMID: 31491676.

6: Zhang Z, Gao W, Zhou L, Chen Y, Qin S, Zhang L, Liu J, He Y, Lei Y, Chen HN, Han J, Zhou ZG, Nice EC, Li C, Huang C, Wei X. Repurposing Brigatinib for the Treatment of Colorectal Cancer Based on Inhibition of ER-phagy. Theranostics. 2019 Jul 9;9(17):4878-4892. doi: 10.7150/thno.36254. eCollection 2019. PubMed PMID: 31410188; PubMed Central PMCID: PMC6691391.

7: Lenderking WR, Lin H, Speck RM, Zhu Y, Huang H, Huang J, Kerstein D, Langer CJ. Patient-reported outcomes and quality of life in advanced ALK+ non-small-cell lung cancer trial of brigatinib (ALTA). Future Oncol. 2019 Aug;15(24):2841-2855. doi: 10.2217/fon-2019-0185. Epub 2019 Jul 31. PubMed PMID: 31364872.

8: Hamilton G, Hochmair MJ. An evaluation of brigatinib as a promising treatment option for non-small cell lung cancer. Expert Opin Pharmacother. 2019 Sep;20(13):1551-1561. doi: 10.1080/14656566.2019.1643839. Epub 2019 Jul 22. Review. PubMed PMID: 31328968.

9: Morgado F, Calvão J, Barata F, Gonçalo M. Phototoxic reaction to brigatinib - a new photosensitizing drug. J Eur Acad Dermatol Venereol. 2019 Dec;33(12):e491-e492. doi: 10.1111/jdv.15818. Epub 2019 Jul 30. PubMed PMID: 31325397.

10: Hochmair M, Weinlinger C, Schwab S, Naber J, Setinek U, Krenbek D, Urban MH, Fabikan H, Watzka S, Koger R, Fazekas A, Bitterlich E, Valipour A, Burghuber OC. Treatment of ALK-rearranged non-small-cell lung cancer with brigatinib as second or later lines: real-world observations from a single institution. Anticancer Drugs. 2019 Aug;30(7):e0787. doi: 10.1097/CAD.0000000000000787. PubMed PMID: 31305295.

11: Tugnait M, Gupta N, Hanley MJ, Sonnichsen D, Kerstein D, Dorer DJ, Venkatakrishnan K, Narasimhan N. Effects of Strong CYP2C8 or CYP3A Inhibition and CYP3A Induction on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers. Clin Pharmacol Drug Dev. 2019 Jul 9. doi: 10.1002/cpdd.723. [Epub ahead of print] PubMed PMID: 31287236.

12: Gaye E, Geier M, Bore P, Guilloïque M, Lucia F, Quéré G, Gouva S, Robinet G, Descourt R. Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis. Lung Cancer. 2019 Jul;133:1-3. doi: 10.1016/j.lungcan.2019.04.013. Epub 2019 Apr 20. PubMed PMID: 31200813.

13: Kawata AK, Lenderking WR, Eseyin OR, Kerstein D, Huang J, Huang H, Zhang P, Lin HM. Converting EORTC QLQ-C30 scores to utility scores in the brigatinib ALTA study. J Med Econ. 2019 Sep;22(9):924-935. doi: 10.1080/13696998.2019.1624080. Epub 2019 Jun 25. PubMed PMID: 31125274.

14: Umbela S, Ghacha S, Matuknauth R, Gause S, Joshee S, Deshmukh RR. Brigatinib: New-generation ALK inhibitor for nonsmall cell lung cancer. Curr Probl Cancer. 2019 Dec;43(6):100477. doi: 10.1016/j.currproblcancer.2019.03.005. Epub 2019 May 6. Review. PubMed PMID: 31109722.

15: Camidge DR, Pabani A, Miller RM, Rizvi NA, Bazhenova L. Management Strategies for Early-Onset Pulmonary Events Associated with Brigatinib. J Thorac Oncol. 2019 Sep;14(9):1547-1555. doi: 10.1016/j.jtho.2019.04.028. Epub 2019 May 18. PubMed PMID: 31108247.

16: Hochmair M, Weinlinger C, Prosch H. Intracranial remission with brigatinib rechallenge as fifth-line ALK inhibition therapy in a lung cancer patient. Anticancer Drugs. 2019 Nov;30(10):1058-1060. doi: 10.1097/CAD.0000000000000800. PubMed PMID: 31033499.

17: Mehlman C, Chaabane N, Lacave R, Kerrou K, Ruppert AM, Cadranel J, Fallet V. Ceritinib ALK T1151R Resistance Mutation in Lung Cancer With Initial Response to Brigatinib. J Thorac Oncol. 2019 May;14(5):e95-e96. doi: 10.1016/j.jtho.2018.12.036. PubMed PMID: 31027750.

18: Bender L, Meyer G, Quoix E, Mennecier B. Ceritinib-related interstitial lung disease improving after treatment cessation without recurrence under either crizotinib or brigatinib: a case report. Ann Transl Med. 2019 Mar;7(5):106. doi: 10.21037/atm.2019.01.24. PubMed PMID: 31019956; PubMed Central PMCID: PMC6462648.

19: Melosky B, Cheema P, Liu G. Brigatinib is another treatment option for patients diagnosed with advanced ALK-positive non-small-cell lung cancer who are treatment-naïve or who have progressed on or are intolerant to crizotinib. Curr Oncol. 2019 Feb;26(1):e119-e120. doi: 10.3747/co.26.4809. Epub 2019 Feb 1. PubMed PMID: 30853819; PubMed Central PMCID: PMC6380641.

20: Ali R, Arshad J, Palacio S, Mudad R. Brigatinib for ALK-positive metastatic non-small-cell lung cancer: design, development and place in therapy. Drug Des Devel Ther. 2019 Feb 8;13:569-580. doi: 10.2147/DDDT.S147499. eCollection 2019. Review. PubMed PMID: 30804663; PubMed Central PMCID: PMC6372006.



Additional Information

Brigatinib was approved in 4/28/2017 to treat patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib