Dacomitinib

Hu Z-Y, et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2024, 314, 124197.

This study examined the binding characteristics of dacomitinib, a potent second-generation tyrosine kinase inhibitor, to human α1-acid glycoprotein (HAG) through multispectral techniques and computational simulations. Fluorescence spectroscopy demonstrated that dacomitinib statically quenches HAG fluorescence by forming a 1:1 complex, with a notable binding constant of 8.95 × 10⁶ M⁻¹ at physiological temperature. Comparative analysis indicated dacomitinib's preferential binding to HAG over bovine serum albumin (BSA). Thermodynamic studies and competitive binding assays revealed that hydrogen bonding and hydrophobic interactions stabilize the HAG-dacomitinib complex. Circular dichroism spectroscopy further confirmed that binding induces minor conformational changes in HAG and diminishes the hydrophobic microenvironment of Trp and Tyr residues. Computationally, molecular docking and molecular dynamics simulations identified key binding residues, substantiating the experimental observations. Notably, Mg²⁺ and Co²⁺ ions synergistically enhanced the binding affinity (Kb) and prolonged the half-life of dacomitinib.

Chen X, et al. European Journal of Pharmacology, 2023, 960, 176046.

To elucidate the therapeutic potential of dacomitinib in non-small cell lung cancer (NSCLC), researchers conducted comprehensive single-cell transcriptome analyses of A549 cancer models, employing both in vitro cultures and in vivo xenografts in nude mice. Single-cell RNA sequencing was utilized to delineate transcriptomic heterogeneity at single-cell resolution, revealing that A549 cells in vitro exhibited diverse subpopulations, including a minor subset characterized by unfolded protein response. This subpopulation emerged as the predominant cluster in A549 xenografts. In contrast to the in vitro resistance to dacomitinib due to EGFR non-activating status, the A549 xenografts demonstrated significant sensitivity to dacomitinib treatment, akin to the response observed in EGFR-activating HCC827 xenografts. Further bulk RNA and protein analyses validated the differential gene expression. Functionally, dacomitinib inhibited the MAPK signaling pathway and enhanced immune responses within the tumor microenvironment. Notably, the phagocytosis checkpoint molecule stanniocalcin-1 (STC1) was downregulated in xenografts upon dacomitinib treatment.