Rewiring Endocannabinoid Pharmacology Through Kinome-Driven Modulation

Abstract

The endocannabinoid system (ECS) orchestrates neural, immune, and metabolic homeostasis; however, its therapeutic translation has been persistently constrained by the psychoactive burden and pharmacodynamic liabilities associated with CB₁ and CB₂ receptor activation. Notably, endogenous cannabinoids fail to reproduce the psychotropic effects of phytocannabinoids, underscoring a fundamental disconnect between physiological ECS signaling and receptor-centric drug design. Beyond classical ligand–receptor paradigms, the ECS operates within kinase-regulated signaling networks that control receptor trafficking, intracellular signal integration, and endocannabinoid biosynthesis and degradation. This review reframes ECS pharmacology through the lens of the kinome, identifying MAPK, AMPK, PKA, PKC, and PI3K/Akt pathways as critical intracellular nodes amenable to therapeutic intervention. We evaluate emerging strategies—including ATP-competitive inhibitors, allosteric modulators, PROTACs, molecular glues, and dual-target hybrid compounds—that enable receptor-independent modulation of ECS function. Proof-of-concept studies across neuroinflammatory, metabolic, and tolerance-related models illustrate the translational potential of this approach. By positioning the kinome as a druggable interface, this framework advances ECS therapeutics beyond surface receptor engagement toward mechanism-informed, scalable, and precision-oriented interventions.

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