Receptor-interacting protein kinase 2 (RIPK2): Structural insights, pathophysiological roles, and medicinal chemistry advances in inhibitor design.

Receptor-interacting protein kinase 2 (RIPK2) is a multifunctional serine/threonine kinase that bridges innate immunity, inflammation, and oncogenic signaling. Downstream of NOD1 and NOD2 receptors, RIPK2 mediates NF-κB and MAPK activation through kinase-dependent and adaptor-driven mechanisms, thereby regulating cytokine production and host defense. Aberrant activation or overexpression of RIPK2 contributes to chronic inflammatory disorders and, in preclinical studies, to multiple cancers, including colorectal, breast, and lung malignancies, highlighting its dual role as a signaling integrator and potential tumor-promoting factor. Recent structural and biochemical studies have elucidated the topology of the RIPK2 kinase domain, revealing key catalytic residues (Lys47, Glu66, Asp164, Met98) and allosteric elements such as the αJ-helix and CARD domain that underpin dimerization, activation, and ubiquitination. These insights have driven the rational design of ATP-competitive, allosteric, and covalent inhibitors with improved potency and selectivity. Clinically approved multikinase inhibitors-including ponatinib, gefitinib, and regorafenib-exhibit off-target RIPK2 inhibition, while selective compounds such as WEHI-345, GSK2983559, CSLP37, UH15-15, and thienopyrimidine derivatives represent key advances in selective blockade. Novel modalities, including XIAP-BIR2 antagonists and PROTAC-based degraders, further expand therapeutic strategies for inflammation-driven diseases and, in preclinical models, cancer. Despite encouraging preclinical data, no RIPK2-specific inhibitor has yet achieved clinical approval due to safety and selectivity challenges. Continued structure-guided optimization, exploration of allosteric and degradation-based mechanisms, and integration into precision-medicine frameworks may ultimately enable safe and effective RIPK2-targeted therapies for inflammatory and autoimmune disorders, while the potential application in oncology remains under preclinical investigation.