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.
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.
