Over the past two decades, anticancer drug discovery has evolved from the development of empirically identified, broadly cytotoxic agents, selected primarily for their ability to kill rapidly proliferating cells with limited mechanistic specificity, toward the rational design of therapies informed by molecular oncology. Historically, most chemotherapeutic drugs were developed based on their ability to suppress rapidly dividing cells, often with limited selectivity between malignant and healthy tissues, leading to significant dose-limiting toxicities.

Current discovery efforts now prioritize a mechanistic understanding of tumor biology, leveraging insights from cancer genomics, proteomics, and functional screening to identify oncogenic drivers and cancer-specific vulnerabilities. This evolution has enabled the development of targeted therapeutics that selectively modulate dysregulated signaling pathways, lineage-dependent survival mechanisms, and noncanonical oncogenic processes, including aberrant post-translational modifications and metabolic reprogramming. In parallel, modern discovery frameworks emphasize early integration of target validation, pharmacodynamic biomarkers, and mechanism-of-action studies, moving beyond reliance on phenotypic cytotoxicity alone. Drug candidates are increasingly assessed based on target engagement and pathway modulation, facilitating patient stratification and rational clinical trial design. Collectively, these advances reflect a redefinition of how anticancer agents are conceived and developed, emphasizing precision, selectivity, and translational relevance. This integrated approach has redesigned the discovery pipeline and continues to inform the development of safer and more effective therapies tailored to the molecular complexity of cancer.

Keywords: Anticancer drug discovery, targeted cancer therapy, rational drug design, structure-based drug discovery, translational pharmacology, mechanism-of-action, drug resistance, tumor heterogeneity