A patent review of DNA polymerase theta (Polθ) targeted therapies (2019–2025)

DNA Polymerase theta (Polθ), a critical multifunctional DNA repair enzyme in the alternative non-homologous end joining (alt-NHEJ) pathway, has recently emerged as a new promising synthetic lethal target for homologous recombination (HR) deficient cancers. Since the first-in-class Polθ polymerase inhibitor entered clinical trials in 2021, this field has witnessed explosive growth in interest, underscored by a surge in Polθ inhibitor patents and nine candidates progressing to clinical trials. This comprehensive patent review focuses on structural features and biochemical profiles of both Polθ inhibitors reported between 2019 and 2025, leveraging patents retrieved from the databases of World Intellectual Property Organization (WIPO), United States Patent and Trademark Office (USPTO), Cortellis Drug Discovery Intelligence, and China National Intellectual Property Administration (CNIPA). The rapid progress of Polθ inhibitors highlights their potential as a synthetic lethal strategy for HR-deficient cancers. Recently, an increasing number of patents and articles on inhibitors targeting Polθ have been published. At present, a total of nine Polθ inhibitors are under study in early clinical trials. Artios’ Polθ inhibitor ART6043 has excellent clinical data. The results of these trials will influence the future development of Polθ inhibitors for HR-deficient cancers.