Optimization of MMP-13 Inhibitor Selectivity to Prevent and Reverse Chemotherapy-Induced Peripheral Neuropathy

Summary

Chemotherapy-induced peripheral neuropathy (CIPN) is a chronic, disabling complication that affects ~70% of cancer patients, often persisting after treatment and severely diminishing the quality of life. Symptoms include pain, numbness, and tingling among others. Current therapies provide only partial pain relief without addressing the underlying nerve damage. Research from our group has identified a conserved mechanism whereby the chemotherapeutic agent, paclitaxel, induces epidermal reactive oxygen species (ROS), leading to activation of matrix metalloproteinase-13 (MMP-13) and subsequent MMP-13 dependent sensory axon degeneration. Importantly, MMP-13 inhibition prevents CIPN onset and restores axon damage across various models, underscoring the translational relevance. This has prompted us to develop proprietary MMP-13 inhibitors for clinical use. This ULINK project aims to (1) refine the selectivity of one selected compound, AVX561, toward MMP-13 over other MMPs, using medicinal chemistry and pharmacokinetic profiling through Dr. Feng’s expertise. (2) We will also evaluate the efficacy of AVX561 and its new analogs in mouse models of acute and chronic CIPN (Dr. Rieger). This work seeks to transform the management of CIPN from transient symptom control to long-term prevention and repair and lay the foundation for clinical translation as the first disease-modifying treatment for chronic CIPN.

Team

Sandra Rieger (Biology), Yangbo Feng (Pharmacology)

Optimization of MMP-13 Inhibitor Selectivity to Prevent and Reverse Chemotherapy-Induced Peripheral Neuropathy