Rational design of next-generation PDK1 modulators: Addressing selectivity and resistance through molecular insights...

3-Phosphoinositide-dependent protein kinase 1 (PDK1) serves as a critical signaling hub regulating cellular proliferation, metabolism, and survival. Its dysregulated activation is strongly linked to cancer, metabolic disorders, and neurodegenerative diseases, establishing small-molecule PDK1 modulators as a major research focus in medicinal chemistry. Early development focused on ATP-competitive inhibitors; however, their clinical utility was limited by off-target effects and suboptimal membrane permeability. Recent structure-based drug design approaches have yielded novel chemotypes. Nevertheless, PDK1 inhibitors face significant challenges, including insufficient selectivity, suboptimal drug-like properties, and emerging mechanisms of therapeutic resistance. This review provides a systematic overview of the development of PDK1 modulators, categorizing them into allosteric binders, ATP-competitive inhibitors, and agents inducing unique DFG-out conformations based on their mechanisms of action and binding modes. Notably, several natural products targeting PDK1 to modulate the PDK1/Akt/mTOR pathway have been identified. Their structural diversity offers valuable insights for the design of next-generation inhibitors with enhanced selectivity and reduced off-target toxicity. We comprehensively analyze the structure-activity relationships (SAR), biological activities, and mechanisms of action of these modulators, while also addressing persistent challenges and therapeutic opportunities in the field. This work offers rational design frameworks and strategic insights for developing novel PDK1-targeted therapeutics with optimized efficacy and safety profiles.