Methoxyamine (DB06328, TRC-102): A Comprehensive Review of its Pharmacology, Clinical Development, and Therapeutic Potential as a Base Excision Repair Inhibitor

1. Executive Summary

[Methoxyamine, also known by its investigational name TRC-102, is a small molecule compound that has garnered attention for its role as an inhibitor of the Base Excision Repair (BER) pathway, a critical DNA repair mechanism. Its primary mechanism involves the formation of stable adducts at apurinic/apyrimidinic (AP) sites in DNA, thereby blocking their repair and leading to the accumulation of DNA damage, ultimately triggering cell death, particularly in cancer cells. The rationale for Methoxyamine's development, spearheaded by TRACON Pharmaceuticals, centers on its potential to potentiate the efficacy of conventional DNA-damaging cancer therapies, such as chemotherapy and radiotherapy, and to overcome acquired resistance to these treatments.][1]

[Clinical development has explored Methoxyamine (TRC-102) across a spectrum of malignancies, including non-small cell lung cancer (NSCLC), glioblastoma, mesothelioma, and various hematologic cancers, predominantly in combination regimens. While some early-phase trials have shown promising response rates, particularly in NSCLC when combined with chemoradiotherapy, the overall clinical journey has been marked by variable outcomes. For instance, a Phase 2 trial in recurrent glioblastoma did not meet its primary efficacy endpoint, although intriguing biomarker signals emerged in a subset of long-term survivors.][4][ The safety profile of Methoxyamine combinations is generally characterized by manageable hematologic and gastrointestinal toxicities.]