SYN818

SYN818 is a novel, orally administered small molecule inhibitor of DNA polymerase theta (Polθ), developed by SynRx Therapeutics. It represents a first-in-human targeted therapy designed to exploit synthetic lethality in homologous recombination-deficient (HRD) cancers, such as those with BRCA mutations. Polθ is an enzyme involved in the microhomology-mediated end joining (MMEJ) pathway for DNA double-strand break repair—a pathway that becomes critical when homologous recombination is impaired. By inhibiting Polθ, SYN818 selectively impairs DNA repair in HRD tumor cells, leading to cell death while sparing normal tissues where Polθ expression is low. Preclinical studies have shown potent anti-tumor activity and synergy with PARP inhibitors and other therapies. The drug has entered Phase 1 clinical trials for advanced or metastatic solid tumors, including breast cancer, ovarian cancer, prostate cancer, and other HRD-positive malignancies[2][3][5][6].