Ladarixin (DB16212): A Comprehensive Review of a Dual CXCR1/2 Allosteric Inhibitor from Preclinical Promise to Clinical Crossroads

Executive Summary

Ladarixin (DB16212) is an orally bioavailable, investigational small molecule that functions as a potent, non-competitive, dual allosteric inhibitor of the C-X-C motif chemokine receptors 1 (CXCR1) and 2 (CXCR2). Its mechanism of action centers on blocking the pro-inflammatory signaling cascade initiated by Interleukin-8 (IL-8), thereby modulating the recruitment and activity of neutrophils and other myeloid cells. This report provides a comprehensive analysis of Ladarixin, from its fundamental pharmacology and extensive preclinical evaluation to its complex clinical development history and current regulatory standing.

Preclinical studies have established a robust and broad therapeutic rationale for Ladarixin. In animal models of Type 1 Diabetes (T1D), it demonstrated the ability to both prevent and reverse autoimmune-driven hyperglycemia by inhibiting insulitis. Furthermore, it showed potential to mitigate long-term diabetic complications independently of glycemic control. In oncology, Ladarixin exhibited multifactorial antineoplastic activity, including direct effects on tumor cells and, more significantly, the ability to remodel the tumor microenvironment. Its capacity to convert immunologically "cold" tumors to "hot" by disrupting myeloid-derived immunosuppression positions it as a promising candidate for combination therapy with checkpoint inhibitors. Its anti-inflammatory effects were also confirmed in various models of respiratory disease, including corticosteroid-resistant asthma.