An in Vitro Assay of hERG K+ Channel Potency for a New EGFR Inhibitor FHND004

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.

Cardiac Safety Assessment of Lazertinib: Findings From Patients With EGFR Mutation-Positive Advanced NSCLC and Preclinical Studies

“…In our study, lazertinib had an IC 50 of 5.3 μM in the hERG cellular patch-clamp assay, whereas an earlier study of osimertinib reported an IC 50 of 0.57 μM in a similar assay. 31 Our preclinical data thus support the idea that lazertinib might have reduced potential for HER2- or hERG-related cardiotoxicity, compared with other TKIs.…”

Potent hERG channel inhibition by sarizotan, an investigative treatment for Rett Syndrome

“…In our prior study of a minimally structured high affinity hERG inhibitor, Cavalli-2, mutation at F656 had greater effects on blocking potency than mutation at either F557 or Y652 [27]. An independent study of a novel EGFR inhibitor FHND004 also found mutation at F656 to attenuate inhibition more than at F557 [48]. Sarizotan is notable in this regard as it is an I hERG inhibitor for which mutation of F557 produces a greater attenuation of inhibition than mutation at the canonical F656 binding residue.…”

Case Report: Torsade de Pointes Induced by the Third-Generation Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitor Osimertinib Combined With Litsea Cubeba

“…EGFR are linked to many potassium channels, i.e., Kv1.3 ( 15 ), Kv10.1 ( 16 ), Kv4.3 ( 17 ), and Kir2.3 ( 18 ), which are modulated by EGFR kinase via phosphorylation of tyrosine in their specific residues. Osimertinib has been proved as a weak inhibitor of the cardiac potassium ion channel, Kv11.1, inhibiting hERG encoded potassium channel function with an in vitro IC50 of 0.69 mM ( 19 ). Spontaneous release of Ca 2 + via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca 2 + release (SOICR), is a common mechanism underlying arrhythmia.…”