Brigatinib (AP-26113)
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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.


Price and Availability

Size
Price

25mg
USD 150
200mg
USD 750
2g
USD 1950
Size
Price

50mg
USD 250
500mg
USD 1050
5g
USD 2950
Size
Price

100mg
USD 450
1g
USD 1250
10g
USD 3950

Brigatinib, purity > 98%, is in stock. The same day shipping out after order is received. Note: the estimated shipping out time for order > 10g may be 2 weeks.


Chemical Structure

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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


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

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

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


Technical Data

Appearance:
Light yellow solid powder

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

Certificate of Analysis:

Safety Data Sheet (MSDS):

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).

Harmonized System Code:
293490


Additional Information

The following public resources have listed a wrong structure for Brigatinib (AP-26113)

1. Some papers:
Such as Onco Targets Ther. 2014 Mar 5;7:375-85., http://www.ncbi.nlm.nih.gov/pubmed/24623980.

2. Wikipedia (https://en.wikipedia.org/wiki/Brigatinib, last visited on 12/9/2015).

3. Sci-Finder Scholar Database: Before December 2015, Sci-Finder Scholar Database also wrongly listed CAS#1197958-12-5 as Brigatinib (AP26113). Now Sci-Finder Scholar Database has corrected.

4. Pubchem: https://pubchem.ncbi.nlm.nih.gov/compound/ap26113, last visited: 12/9/2015.
_________________________________________________________________________________________________________
--------------------------------------------------- More information related to AP26113 bioactivities---------------------------------------------
_________________________________________________________________________________________________________
AP26113 is a potent and selective ALK inhibitor. AP26113 induced tumor regression in BaF3 xenograft model expressing EML4-ALK, and EML4-ALK harboring G1269S and L1196M (gatekeeper) mutations. In preclinical studies, AP26113 was shown to be active against all 9 clinically-identified crizotinib-resistant mutants tested. AP26113 is also a potent, reversible inhibitor of activated and T790M-mutant EGFR, yet it does not inhibit the native enzyme [94]. A phase I/II study was initiated (NCT01449461) to evaluate AP26113 as a dual ALK/mutant EGFR inhibitor. As of 14 Jan 2013, 44 patients were enrolled including 37 with NSCLC. In the dose escalation phase (30-300 mg), two dose limiting toxicities were observed, grade 3 ALT elevations at 240 mg and grade 4 dyspnea at 300 mg. The recommended phase II dose was identified as 180 mg. The most common adverse effects were nausea (45%), fatigue (39%), diarrhea (27%). Among 18 evaluable ALK+ patients, four out of 5 patients with CNS lesions showed improvement on follow up imaging, including one patient resistant to crizotinib and ceritinib. Sixteen patients had EGFR mutation (EGFRm). Of 12 patients with EGFRm, one patient responded at 120 mg (duration 21 weeks, ongoing) and 6 patients had stable disease (2 ongoing, duration 7 and 31 weeks, respectively). In a later update, 114 pts were enrolled: 65 in phase 1 (30–300 mg) and 49 in phase 2 (180 mg) [93]. There were 106 pts with NSCLC. The most common treatment-emergent AEs (20%) were similar to the previous report. Early onset of pulmonary symptoms (dyspnea with hypoxia and/or findings on imaging) were observed in 6/45 (13%) pts at 180 mg QD. These symptoms needed urgent intervention. The respiratory symptoms were not observed at 90 mg QD (n = 8) or in the lead-in dose cohort (n = 19; initiated at 90 mg QD, escalated to 180 mg QD after 1 wk). Therefore, further enrollment with this dose escalation scheme, and an additional cohort of 90 mg QD without escalation were being added. Among 38 evaluable ALK+ NSCLC pts who had prior crizotinib, 24 (63%) reported response, including one CR. Six of 10 pts enrolled with untreated or progressing brain metastases showed response in brain, including 4 with complete resolution; 2 stable disease, 2 progressed; AP26113 has promising anti-tumor activity in pts with crizotinib-resistant ALK+ NSCLC, including pts with brain metastases. A randomized phase 2 trial of AP26113 comparing 90 mg QD vs. 90 mg QD escalating to 180 mg QD in crizotinib-resistant ALK+ NSCLC was planned. (copied from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349797/)


References

1: Noonan SA, Camidge DR. PROFILE 1014: lessons for the new era of lung cancer clinical research. Transl Lung Cancer Res. 2015 Oct;4(5):642-648. PubMed PMID: 26629438; PubMed Central PMCID: PMC4630507.

2: Correction: Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma. Mol Cancer Res. 2015 Oct;13(10):1441. doi: 10.1158/1541-7786.MCR-15-0277. Epub 2015 Sep 29. PubMed PMID: 26420623.

3: Iams WT, Lovly CM. Anaplastic Lymphoma Kinase as a Therapeutic Target in Non-Small Cell Lung Cancer. Cancer J. 2015 Sep-Oct;21(5):378-82. doi: 10.1097/PPO.0000000000000142. PubMed PMID: 26389762.

4: Toyokawa G, Seto T, Takenoyama M, Ichinose Y. Insights into brain metastasis in patients with ALK+ lung cancer: is the brain truly a sanctuary? Cancer Metastasis Rev. 2015 Dec;34(4):797-805. doi: 10.1007/s10555-015-9592-y. PubMed PMID: 26342831; PubMed Central PMCID: PMC4661196.

5: Iragavarapu C, Mustafa M, Akinleye A, Furqan M, Mittal V, Cang S, Liu D. Novel ALK inhibitors in clinical use and development. J Hematol Oncol. 2015 Feb 27;8:17. doi: 10.1186/s13045-015-0122-8. PubMed PMID: 25888090; PubMed Central PMCID: PMC4349797.

6: Viala M, Brosseau S, Planchard D, Besse B, Soria JC. [Second generation ALK inhibitors in non-small cell lung cancer: systemic review]. Bull Cancer. 2015 Apr;102(4):381-9. doi: 10.1016/j.bulcan.2015.02.016. Epub 2015 Mar 25. Review. French. PubMed PMID: 25819217.

7: Mologni L, Ceccon M, Pirola A, Chiriano G, Piazza R, Scapozza L, Gambacorti-Passerini C. NPM/ALK mutants resistant to ASP3026 display variable sensitivity to alternative ALK inhibitors but succumb to the novel compound PF-06463922. Oncotarget. 2015 Mar 20;6(8):5720-34. PubMed PMID: 25749034; PubMed Central PMCID: PMC4467397.

8: Fontana D, Ceccon M, Gambacorti-Passerini C, Mologni L. Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK. Cancer Med. 2015 Jul;4(7):953-65. doi: 10.1002/cam4.413. Epub 2015 Feb 26. PubMed PMID: 25727400; PubMed Central PMCID: PMC4529334.

9: Pall G. The next-generation ALK inhibitors. Curr Opin Oncol. 2015 Mar;27(2):118-24. doi: 10.1097/CCO.0000000000000165. Review. PubMed PMID: 25588040.

10: Ma L, Zhang S. [Current status of targeted therapy for anaplastic lymphoma kinase in non-small cell lung cancer]. Zhongguo Fei Ai Za Zhi. 2014 Dec;17(12):850-4. doi: 10.3779/j.issn.1009-3419.2014.12.05. Review. Chinese. PubMed PMID: 25539610.

11: Stasi I, Cappuzzo F. Second generation tyrosine kinase inhibitors for the treatment of metastatic non-small-cell lung cancer. Transl Respir Med. 2014 Jan 6;2:2. doi: 10.1186/2213-0802-2-2. eCollection 2014. PubMed PMID: 25505694; PubMed Central PMCID: PMC4215821.

12: Ceccon M, Mologni L, Giudici G, Piazza R, Pirola A, Fontana D, Gambacorti-Passerini C. Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK-Positive Anaplastic Large Cell Lymphoma. Mol Cancer Res. 2015 Apr;13(4):775-83. doi: 10.1158/1541-7786.MCR-14-0157. Epub 2014 Nov 24. PubMed PMID: 25421750.

13: Awad MM, Shaw AT. ALK inhibitors in non-small cell lung cancer: crizotinib and beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39. Review. PubMed PMID: 25322323; PubMed Central PMCID: PMC4215402.

14: Nguyen KS, Neal JW, Wakelee H. Review of the current targeted therapies for non-small-cell lung cancer. World J Clin Oncol. 2014 Oct 10;5(4):576-87. doi: 10.5306/wjco.v5.i4.576. Review. PubMed PMID: 25302162; PubMed Central PMCID: PMC4129523.

15: Isozaki H, Yasugi M, Takigawa N, Hotta K, Ichihara E, Taniguchi A, Toyooka S, Hashida S, Sendo T, Tanimoto M, Kiura K. A new human lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. Jpn J Clin Oncol. 2014 Oct;44(10):963-8. doi: 10.1093/jjco/hyu110. Epub 2014 Aug 28. PubMed PMID: 25170107.

16: Vijayvergia N, Mehra R. Clinical challenges in targeting anaplastic lymphoma kinase in advanced non-small cell lung cancer. Cancer Chemother Pharmacol. 2014 Sep;74(3):437-46. doi: 10.1007/s00280-014-2517-6. Epub 2014 Aug 19. Review. PubMed PMID: 25135623.

17: Rossi A, Maione P, Sacco PC, Sgambato A, Casaluce F, Ferrara ML, Palazzolo G, Ciardiello F, Gridelli C. ALK inhibitors and advanced non-small cell lung cancer (review). Int J Oncol. 2014 Aug;45(2):499-508. doi: 10.3892/ijo.2014.2475. Epub 2014 May 29. Review. PubMed PMID: 24889366.

18: Iwama E, Okamoto I, Harada T, Takayama K, Nakanishi Y. Development of anaplastic lymphoma kinase (ALK) inhibitors and molecular diagnosis in ALK rearrangement-positive lung cancer. Onco Targets Ther. 2014 Mar 5;7:375-85. doi: 10.2147/OTT.S38868. eCollection 2014. Review. PubMed PMID: 24623980; PubMed Central PMCID: PMC3949762.

19: Perez CA, Velez M, Raez LE, Santos ES. Overcoming the resistance to crizotinib in patients with non-small cell lung cancer harboring EML4/ALK translocation. Lung Cancer. 2014 May;84(2):110-5. doi: 10.1016/j.lungcan.2014.02.001. Epub 2014 Feb 8. Review. PubMed PMID: 24598368.

20: Solomon B, Wilner KD, Shaw AT. Current status of targeted therapy for anaplastic lymphoma kinase-rearranged non-small cell lung cancer. Clin Pharmacol Ther. 2014 Jan;95(1):15-23. doi: 10.1038/clpt.2013.200. Epub 2013 Oct 3. Review. PubMed PMID: 24091716.