Abstract
FHND004 is a newly synthesized epidermal growth factor receptor (EGFR) inhibitor for the treatment of non-small cell lung cancer (NSCLC). The aim of the present study was to investigate the impacts of FHND004 on human ether-à-go-go-related gene (hERG) K+ channels and the molecular mechanisms underlying of its action. Whole-cell patch clamp recording was performed on wild type (WT), mutant hERG channels heterologously expressed in human embryonic kidney (HEK) 293 cells or IKr endogenously expressed in HL-1 cells, respectively. FHND004 inhibited hERG K+ currents in a concentration-dependent manner with IC50 values of 8.46 ± 0.33 μM in HEK293 cells and 7.52 ± 1.27 μM in HL-1 cells, respectively. However, the inhibitory potency of FHND004 on hERG channels was significantly less than its precursor AZD9291. FHND004-induced inhibition was state-dependent with a preference within open state, but did not alter other kinetics including activation, inactivation, and recovery from inactivation or deactivation. In addition, FHND004 exhibited more potent inhibitory effects on WT/A422T and WT/H562P-hERG, two known long QT syndrome (LQTS) associated KCNH2 mutations, than WT alone. Mutations of the residues at pore regions (F656C, Y652A, S624A, and F557L) in hERG channels attenuated block effects of FHND004. Taken together, our results demonstrate the evidence that FHND004 is a less potent hERG blocker than its precursor AZD9291. There is, however, a need for caution in the potential use of FHND004 for treating NSCLC patients, especially in those with other concurrent triggering factors.
Highlights
The human ether-à-go-go-related gene encodes the pore-forming subunit of the rapid delayed rectifier K+ channels, which conduct the rapid delayed rectifier K+ current and play an essential role in the repolarization phase of the cardiac action potential
Epidermal growth factor receptor (EGFR) belongs to the receptor tyrosine kinase (RTK) super-family, which has a close relationship with the development of many human cancers (Hynes and Lane, 2005), especially in non-small cell lung cancer (NSCLC; Suzuki et al, 2005; Ellis et al, 2009; Rosell et al, 2009), making it an important anticancer target
To investigate the effects of FHND004 on IhERG, wholecell patch clamp recordings were performed on HEK293 cells heterologously expressing human ether-à-go-go-related gene (hERG) channels
Summary
The human ether-à-go-go-related gene (hERG) encodes the pore-forming subunit of the rapid delayed rectifier K+ channels, which conduct the rapid delayed rectifier K+ current (referred as IKr; Gutman et al, 2003) and play an essential role in the repolarization phase of the cardiac action potential. Inherited mutations of hERG can induce long QT syndrome (LQTS), a disorder of cardiac repolorization which predisposes affected individuals to life-threatening arrhythmias. First- and second-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) erlotinib (Tarceva), gefitinib (Iressa), afatinib, and dacomitinib have been used in clinic for the treatment of different cancers, offering new therapeutic approaches and an effective long-term cancer therapy (Slamon et al, 2001; Perez et al, 2014). The morbidity of diarrhea, rash, and cardiotoxicity increases with escalating doses of AZD9291 (Gao et al, 2016). To overcome these drawbacks, a novel compound FHND004 is synthesized based on the structure of AZD9291 with a modified pyrimidine ring and an expanded indole ring. Animal-based toxicity studies have shown that the adverse effects of FHND004 are significantly less intense than that of AZD9291, even with the increase of doses (Zhang et al, 2017)
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