AP26113

The Uses of AP26113

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.