A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non–Small Cell Lung Cancer

Abstract

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non–small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08–178–01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08–178–01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08–178–01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08–178–01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08–178–01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification. Significance: This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.

Analysis of the multi-physiological and functional mechanism of wheat alkylresorcinols based on reverse molecular docking and network pharmacology

“…It has been suggested that the interaction between the inhibitor and SER783 may be responsible for the selectivity of ERBB2 (HER2). 59 Moreover, the amino acid residues LEU726, VAL734, ALA751 and LEU852 can form Pi-alkyl with the benzene ring of the compound.…”

Synthesis, Anticancer Activity and Molecular Docking Studies of Novel N-Mannich Bases of 1,3,4-Oxadiazole Based on 4,6-Dimethylpyridine Scaffold

“…Docking studies were performed to assess the binding affinity of compounds 3 – 12 and the reference drugs to the selected receptors: cMet (PDB code: 3RHK) [ 52 ], EGFR (PDB code: 5GTY) [ 53 ], HER2 (PDB code: 7JXH) [ 54 ] and hTrkA (PDB code: 6PL2) [ 55 ]. The four chosen receptors are well known for their importance in cancer progression and metastasis.…”

“…The four chosen receptors are well known for their importance in cancer progression and metastasis. The ligands denoted as M97 [ 52 ], 816 [ 53 ], VOY [ 54 ] and OOM [ 55 ] were re-docked to the receptors. The positions of the co-crystallized ligands with the lowest binding affinity values were selected and presented in Figure 8 .…”

“…The structures of four receptors denoted as: cMet (PDB code: 3RHK) [ 52 ], EGFR (PDB code: 5GTY) [ 53 ], HER2 (PDB code: 7JXH) [ 54 ] and hTrkA (PDB code: 6PL2) [ 55 ] were used in the flexible docking study. They were taken from the Protein Data Bank (PDB) [ 59 ].…”

Structural analysis of the macrocyclic inhibitor BI-4020 binding to EGFR kinase

“…The kinase domains of EGFR and HER2, were expressed and purified as previously described. 3,30,31 Mutations were introduced via PCR and verified by Sanger sequencing. Briefly, insect cells infected with recombinant baculovirus were pelleted and resuspended in buffer, sonicated, clarified via ultracentrifugation, and purified using Ni-NTA agarose beads.…”