Brigatinib (AP26113)

Alias: AP-26113; AP 26113; Brigatinib-analog; AP26113; Brigatinib; Alunbrig.
Cat No.:V0607 Purity: ≥98%
Brigatinib (formerly AP26113;AP-26113; ALK-IN-1; trade name:Alunbrig) is an orally bioavailable, FDA-approved and selective ALK (anaplastic lymphoma kinase) inhibitor with potential antineoplastic activity.
Brigatinib (AP26113) Chemical Structure CAS No.: 1197953-54-0
Product category: ALK
This product is for research use only, not for human use. We do not sell to patients.
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Product Description

Brigatinib (formerly AP26113; AP-26113; ALK-IN-1; trade name: Alunbrig) is an orally bioavailable, FDA-approved and selective ALK (anaplastic lymphoma kinase) inhibitor with potential antineoplastic activity. In a cell-free assay, it inhibits ALK with an IC50 of 0.62 nM. In 2017, the FDA approved brgatinib for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) that is positive for anaplastic lymphoma kinase (ALK), who have progressed or are intolerant to crizotinib. It was shown that brgatinib could overcome the L1196M mutation-mediated crizotinib resistance. A tyrosine kinase receptor called anaplastic lymphoma kinase (ALK) has been linked to a number of solid and hematologic malignancies. ALK mutations are found in roughly 5–7% of cases of neuroblastoma; however, in the group of patients who relapse, the percentage of ALK-positive patients rises noticeably. An analog of AP26113 binds to EGFR and its mutant forms, inhibiting EGFR as well as ALK kinase and ALK fusion proteins. This inhibits the signaling pathways of ALK kinase and EGFR kinase, which in turn prevents tumor cell growth in tumor cells that are vulnerable to it. Currently undergoing evaluation in a global phase 2 registration trial, brgatinib is the most clinically advanced phosphine oxide-containing drug candidate to date.

Biological Activity I Assay Protocols (From Reference)
Targets
ALK (IC50 = 0.37 nM); ROS1 (IC50 = 1.9 nM); FLT3 (IC50 = 2.1 nM); IGF1R (IC50 = 24.9 nM); EGFR(C797S/del19) (IC50 = 39.9 nM)
ln Vitro

Brigatinib significantly reduces the in vitro kinase activity of all five tested mutant variants, including G1202R (IC50, 0.6-6.6 nM), and ALK (IC50, 0.6 nM). Only 11 more native or mutant kinases with an IC50 <10 nM are inhibited by brentinib, indicating a high degree of selectivity. These consist of FLT3, ROS1, and the mutant forms of EGFR (L858R; IC50, 1.5-2.1 nM) and FLT3 (D835Y). Brigatinib does not inhibit MET (IC50 >1000 nM), but it shows more moderate activity against native EGFR, IGF1R, and INSR (IC50, 29-160 nM), as well as EGFR with a T790M resistance mutation (L858R/T790M). Brigatinib inhibits ALK and ROS1 in cellular assays, with IC50 values of 14 and 18 nM, respectively. Brigatinib inhibits EGFR and FLT3 mutant variants with 15–35 fold lower potency (IC50, 211-489 nM) and inhibits FLT3 and IGF-1R with about an 11-fold lower potency (IC50, 148–158 nM). Using GI50 values ranging from 503 to 2,387 nM, brentinib inhibits the growth of three ALK-negative ALCL and NSCLC cell lines[1]. With an IC50 of 75.27 ± 8.89 nM, brentinib inhibits ALK activity and stops the growth of ALK-dependent neuroblastoma cell lines. Both the ALK-I1171N and the ALK-G1269A mutant receptors are inhibited by brentinib at 10 and 4 nM, respectively[3].

ln Vivo
Brigatinib (10, 25, or 50 mg/kg once daily, p.o.) causes a dose-dependent inhibition of tumor growth in ALK+ Karpas-299 (ALCL) and H2228 (NSCLC) xenograft mouse models. Comparing brentinib to PF-02341066, mice with ALK+ brain tumors have a significantly higher survival rate[1]. A mouse model of non-small cell lung cancer showed tumor regressions in response to bogatinib (10, 25, 50 mg/kg, p.o.) demonstrating dose-dependent antitumor activity[2].
Enzyme Assay
A HotSpotSM kinase profile of 289 kinases is carried out in vitro. The experiment is carried out with brigatinib concentrations ranging from 0.05 nM to 1 μM in the presence of 10 μM [33P]-ATP.
Cell Assay
The specified inhibitors are serially diluted and added to each well containing 15,000 cells. Resazurin measures the viability of the cells after 72 hours. By fitting data to an equation of log (inhibitor concentration) vs. normalized response (variable slope), IC50 values are determined using GraphPad Prism 6.0. Every experiment is carried out in two copies and at least three times.
Animal Protocol
Mice: (1) Female SCID/beige mice, aged eight to ten weeks, receive intravenous injections of 5x106 H3122 cells each. After the tumor size reaches approximately 300 mm3 on day zero, the mice are randomized into ten treatment groups. Treatments are taken orally at a dose volume of 10 mL/kg for a maximum of 21 days in a row. Tumors under the skin are measured twice or three times a week. The formula (L×W2)/2 is used to calculate the tumor volume (in mm3). The animal is put to sleep by CO2 asphyxiation when a tumor weighs 10% of its body weight. (2) Female SCID/beige mice, aged eight to ten weeks, receive subcutaneous injections of 2.5 ×106 Karpas-299 cells per mouse. After the tumors reach approximately 180 mm3 on day zero, the mice are randomly assigned to one of ten treatment groups. Oral treatment is given for 14 days in a row at a dose volume of 10 mL/kg. The measurement and computation of tumor volume follow the guidelines for the H3122 model.
References

[1]. 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.

[2]. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem. 2016 May 26;59(10):4948-64.

[3]. 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.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C₂₉H₃₉CLN₇O₂P
Molecular Weight
584.09
Exact Mass
583.26
Elemental Analysis
C, 59.63; H, 6.73; Cl, 6.07; N, 16.79; O, 5.48; P, 5.30
CAS #
1197953-54-0
Appearance
Light yellow solid powder
SMILES
CN1CCN(CC1)C2CCN(CC2)C3=CC(=C(C=C3)NC4=NC=C(C(=N4)NC5=CC=CC=C5P(=O)(C)C)Cl)OC
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)
Chemical Name
5-chloro-4-N-(2-dimethylphosphorylphenyl)-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine
Synonyms
AP-26113; AP 26113; Brigatinib-analog; AP26113; Brigatinib; Alunbrig.
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~45 mg/mL (~85.1 mM)
Water: <1 mg/mL
Ethanol: ~106 mg/mL (~200.4 mM)
Solubility (In Vivo)
NMP+polyethylene glycol 300 (10+90, v+v): 1 mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.7121 mL 8.5603 mL 17.1206 mL
5 mM 0.3424 mL 1.7121 mL 3.4241 mL
10 mM 0.1712 mL 0.8560 mL 1.7121 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT04223596 Active
Recruiting
Drug: Brigatinib Lung Cancer
NSCLC
Fundación GECP May 4, 2020 Phase 2
NCT03535740 Active
Recruiting
Drug: Brigatinib ALK-positive Advanced NSCLC Ariad Pharmaceuticals January 31, 2019 Phase 2
NCT03596866 Active
Recruiting
Drug: Brigatinib
Drug: Alectinib
ALK+ Advanced NSCLC Takeda April 19, 2019 Phase 3
NCT04074993 Active
Recruiting
Drug: Brigatinib Non Small Cell Lung Cancer JI-YOUN HAN May 15, 2020 Phase 2
NCT05361564 Not yet recruiting Drug: Brigatinib Non-small Cell Lung Cancer Yonsei University June 2022 Phase 2
Biological Data
  • AP26113

    Two different ALK kinase inhibitors, NVP-TAE684 and AP26113, overcome crizotinib resistance in H3122 CR cells. Proc Natl Acad Sci U S A. 2011 May 3; 108(18): 7535–7540.


    AP26113

  • AP26113

    Effect of brigatinib in a xenograft neuroblastoma model.2016 May 17;7(20):29011-22.

  • AP26113

    Effect of brigatinib on ALK gain-of-function rough eye phenotypes in aDrosophilaALK model.2016 May 17;7(20):29011-22.

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