DNA polymerase theta (POLQ) (POLQ)

DNA polymerase theta (POLQ) is a specialized A-family DNA polymerase that plays a critical role in the microhomology-mediated end joining (MMEJ) pathway, an alternative DNA double-strand break repair mechanism. While POLQ expression is nearly undetectable in most healthy tissues, it is significantly upregulated in various cancers, particularly those with defects in homologous recombination (HR) repair, such as BRCA1 or BRCA2 mutations [26, 28, 30]. This differential expression makes POLQ a highly attractive therapeutic target for synthetic lethality, as its inhibition selectively triggers cell death in HR-deficient tumor cells while sparing normal cells [27, 29, 31]. Biotech companies like SynRx Therapeutics have developed small-molecule inhibitors, such as SYN818 (often referred to as SY001 or "Undisclosed Target X" in early development), to exploit this vulnerability [11, 13, 20]. These inhibitors block the enzymatic activity of POLQ, preventing the repair of DNA lesions that HR-deficient cells rely on, thereby leading to catastrophic DNA damage and apoptosis [35, 38]. Clinical and preclinical studies are currently evaluating POLQ inhibitors as monotherapies or in combination with PARP inhibitors to overcome resistance in solid tumors [30, 34].

Other names

Undisclosed Target XPOLQDNA polymerase thetaPolymerase (DNA) thetaSY001 (SynRx Therapeutics)

Inhibition of DNA polymerase theta enzymatic activity, blocking the microhomology-mediated end joining (MMEJ) pathway and inducing synthetic lethality in homologous recombination (HR)-deficient cells.