AP26113 Chemical Properties

Boiling point:

737.6±70.0 °C(Predicted)

Density 

1.29±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

≥26.45 mg/mL in DMSO; insoluble in H2O; ≥55.9 mg/mL in EtOH

form 

solid

pka

9.27±0.20(Predicted)

color 

White to off-white

CAS DataBase Reference

1197958-12-5

AP26113 Usage And Synthesis

Description

AP26113 (also known as Brigatinib) is an investigated small molecule for targeted cancer therapy. It is a potent dual inhibitor of anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR). It is mainly under investigation for its treatmentefficacy on non-small cell lung cancer (NSCLC) where ALK is activated and EGFP mutations frequently occur. 

Biological activity

AP26113 is a kind of effective ALK inhibitor with an IC50 of 0.62 nM, being able to overcome the L1196M mutation-mediated Crizotinib resistance; Phase 2.

In vitro study

AP26113 is highly effective in treating the sensitive-type and resistant-type H3122 cells, being able to reduce cell growth, inhibit the ALK phosphorylation and induce the apoptosis. This effect is in a dose-dependent manner. AP26113 acts on the H3122 and H3122 CR cells, reducing p-ALK with an IC50 of 7.4 and 16.8 nM, respectively. AP26113 acts on Ba/F3 cells expressing wild-type or mutant EML4-ALK, reducing the number of cells with an IC50 of 10 nM and 24 nM, respectively. AP26113 inhibits the growth of SU-DHL-1, H3122 and Ba/F3-EML4-ALK v1 cell lines with GI50 values of 9 nM, 4 nM and 13 nM, respectively. AP26113 acts on Karpas-299, SU-DHL-1 and L-82 cell lines through inhibiting ALK phosphorylation with an IC50 of 3.2 nM, 1.5 nM and 2.1 nM, respectively. AP26113 acts on Karpas-299 and H3122 cells and inhibits ALK and ERK phosphorylation in a dose-dependent manner. AP26113 acts on Ba/F3 cell lines (including wild-type EML4-ALK) and Ba/F3 cell lines (containing mutant EML4-ALK G1269S) and inhibits cell growth with an IC50 of 11 nM and 16 nM, respectively. AP26113 acts on Ba/F3 cell line (including wild-type EML4-ALK) and Ba/F3 cell line (containing mutant EML4-ALK E1210K), inhibits cell growth and inhibits ALK phosphorylation with IC50 of 74 nM and 335 nM, respectively. AP26113 (10 mg/kg-75 mg/kg) was effective in the EML4-ALK mutant mouse model of anti-PF-02341066.
AP26113 acts on the tumor expressing wild-type EMLA-ALK, or with G1269S and L1196M mutation, inducing the tumor regression. AP26113 acts on EGFR-DEL-expressing Ba/F3 cells and inhibits EGFR phosphorylation and activation with an IC50 of 75 nM and 114 nM, respectively. AP26113 acts on Ba/F3 cells expressing EGFR-DEL/T790M and inhibits EGFR phosphorylation and viability with the IC50 of 15 and 281 nM, respectively. AP26113 acts on the NSCLC cell line expressing EGFR-DEL (HCC827), inhibits EGFR phosphorylation. It has an IC50 of 62 nM, and inhibits cell growth as well with a GI50 of 165 nM. AP26113 acts on the HCC827 cell line expressing EGFR-DEL/T790M, inhibits EGFR phosphorylation with an IC50 of 59 nM and inhibits cell growth with a GI50 of 245 nM. AP26113 acts on HCC78 NSCLC cells and inhibits the signaling and proliferation of SLC34A2-ROS in a dose-dependent manner.

In vivo studies

AP26113 (<50 mg/kg) can act on the Karpas-299 xenograft tumor model of mice, inhibiting the p-ALK in a dose-dependent manner. AP26113 (<50 mg/kg) acts on Karpas-299 xenograft tumor model and H3122 xenograft tumor model in mice, inhibiting the tumor growth in a dose-dependent manner. AP26113 has excellent properties, including moderate plasma protein binding in vitro (acting in human, rat, mouse, respectively, 47%, 70% and 76%). It has almost no effect on the main CYP subtype. Treatment of AP26113 (10 mg/kg) on rats can give good tolerance. The Cmax is 2587 ng/mL; the AUC is 41120 hr. ng/mL. AP26113 (25 mg/kg) was administered to transplanted tumor mice models bearing HCC827 (EGFR-DEL) or HCC827 (EGFR-DEL/T790M), leading to tumor regression.

Pharmacological mechanism

Brigatinib (AP26113) is a tyrosine kinase inhibitor with in vitro activity against a number of kinases, including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), FLT-3, and also epidermal growth factor receptor (EGFR) deletion and point mutations. Autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling proteins STAT3, AKT, ERK1/2, and S6 is inhibited by Brigatinib in vitro and in vivo.
Brigatinib inhibited growth of various anaplastic large cell lymphoma (ALCL) and NSCLC cell lines expressing NPM-ALK or EML4-ALK fusions [growth inhibition of 50% of cells (GI50) 4–31 nmol/L]; the ALK phosphorylation IC50 of the drug in these cell lines was 1.5–12 nmol/L. GI50 values for Brigatinib ranged between 503 and 2387 nmol/L in 3 ALK-negative ALCL and NSCLC cell lines [2].

References

Gras, J. "Brigatinib. ALK and mutant EGFR inhibitor. Treatment of NSCLC." Drugs of the Future 40.5(2015):287.
Camidge, D. R., et al. "Safety and efficacy of brigatinib (AP26113) in advanced malignancies, including ALK+ non-small cell lung cancer (NSCLC)." (2015).
Gettinger, S. N., et al. "56 Efficacy and safety of brigatinib (AP26113) in ALK+ NSCLC: phase 1/2 trial results." Lung Cancer 91.1(2016):S20-S21.
https://en.wikipedia.org/wiki/Brigatinib

Uses

AP 26113 is a potent anaplastic lymphoma kinase (ALK) inhibitor. It is also an epidermal growth factor (EGFR) receptor tyrosine kinase inhibitor used for treatment of lung cancer.

Biological Activity

ap26113 is a novel, synthetic, orally available small-molecule inhibitor of anaplastic lymphoma kinase (alk), which is a receptor tyrosine kinase in the insulin receptor superfamily, with half maximal inhibitory concentration ic50 ranging from 5 nmol/l to 11 nmol/l. ap26113 is also capable of inhibiting the alk tyrosine kinase gatekeeper mutation l1196m (ic50: 15 nmol/l to 45 nmol/l), mutant epidermal growth factor receptor (egfr) containing the gatekeeper t790m mutation and c-ros oncogene 1 (ros1). moreover, ap26113 has been found to be active against h3122 cells (both sensitive and resistant) and ba/f3 cells harboring native or mutant eml4-alk (ic50: 10 nm and 24 nm respectively).

Enzyme inhibitor

This potent ALK inhibitor (FW = 529.02 g/mol; CAS 1197958-12-5; Solubility: 45 mg/mL DMSO; <1 mg/mL H2O), also named 5-chloro-N2-[4-[4-(dimethylamino)-1-piperidinyl]-2-methoxyphenyl]-N4-[2-(dimethyl- phosphinyl)phenyl]-2,4-pyrimidinediamine, inhibits wild type Lymphoma Kinase, or ALK (Ki = 0.62 nM) and overcomes crizotinib resistance in non- small cell lung cancers harboring the fusion oncogene EML4-ALK. Cells often develop the L1196M gatekeeper mutation within the kinase domain, a changes that renders them resistant to crizotinib, even at higher drug doses (1 μM). AP26113 is highly active against these resistant cancer cells, both in vitro and in vivo.

target

ALK

References

[1]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.
[2]katayama r1, khan tm, benes c, lifshits e, ebi h, rivera vm, shakespeare wc, iafrate aj, engelman ja, shaw at. therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene eml4-alk. proc natl acad sci u s a. 2011 may 3;108(18):7535-40. doi: 10.1073/pnas.1019559108. epub 2011 apr 18.

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