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• 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].

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• 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 ;

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