Repurposing Clinical TKIs as CHK1 Inhibitors for SCLC: A Structure-Based Evaluation

OpenAlex İngilizce

Objective: Small cell lung cancer (SCLC) is characterized by near-universal Tumor Protein p53 (TP53) / Retinoblastoma 1 (RB1) loss, MYC-mediated transcriptional reprogramming, and profound replication stress. These two factors together create a critical dependence on the Ataxia Telangiectasia and Rad3-related (ATR)– Checkpoint Kinase 1 (CHK1) axis for survival under DNA damage. Although some selective CHK1 inhibitors have reached early-phase clinical trials, dose-limiting toxicities have so far hindered regulatory approval. In this context, we aimed to investigate whether U.S. Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved tyrosine kinase inhibitors (TKIs), initially developed against Breakpoint Cluster Region (BCR)–Abelson (ABL), Vascular Endothelial Growth Factor Receptor (VEGFR), Epidermal Growth Factor Receptor (EGFR), and related kinases, exhibit favorable binding profiles against CHK1 and are therefore rational candidates for drug repurposing in SCLC. Method: Structure-based docking simulations were performed on the human CHK1 crystal structure (PDB ID: 4HYI) using AutoDock Vina. A focused library of 20 validated anticancer TKIs was generated, prioritizing ATP-competitive, aromatic heterocyclic scaffolds with known activity against kinase catalytic pockets and, where possible, prioritizing interaction with DNA damage response kinases. Ligands and receptors were subjected to standard preparation protocols that maintain conformational integrity, and their docking poses were examined based on ΔG_bind values, the occupancy profile of the hydrophobic and polar subpockets of the ATP binding cleft, and the contact architectures formed along the hinge–gatekeeper–solvent-front axis. Results: All 20 TKIs exhibited significant affinity for CHK1, with ΔG_bind values ranging from -7.79 to -11.38 kcal/mol. Imatinib, tucatinib, dacomitinib, pazopanib, afatinib, lapatinib, and sunitinib formed the highest-scoring subset, exhibiting broad hydrophobic complementarity to the CHK1 ATP pocket and conserved hydrogen bonding with residues near the hinge. Imatinib, in particular, achieved optimal binding energy and a dense 3D interaction network encompassing the hinge, deep hydrophobic subpockets, and solvent-exposed polar regions. Conclusion: The data demonstrated that the CHK1 ATP binding site is structurally compatible with various clinically used TKIs and that imatinib-like and indolinone-based scaffolds can achieve particularly stable binding modes. These findings support the notion that CHK1-directed drug repurposing is a biologically consistent and structurally feasible strategy in SCLC. However, given that the docking approach provides a structurally static assessment, the results require additional validation through molecular dynamics simulations, biochemical inhibition tests, and SCLC-specific preclinical models.