Discovery of SY-589, a Highly Potent and Orally Bioavailable Polθ Helicase Inhibitor for the Treatment of HR-Deficient Tumors

DNA
polymerase theta (Polθ), which mediates microhomology-mediated
end joining (MMEJ) in homologous recombination-deficient (HRD) cancers,
has recently emerged as a compelling synthetic lethal target. Combining
Polθ inhibition with PARP inhibitors represents a promising
strategy to overcome PARP inhibitor resistance. Here, we present the
discovery of SY-589, a highly potent (ATPase IC50 = 2.29 nM), selective (selectivity index >1800), and orally bioavailable
(F = 107%) Polθ helicase inhibitor, which exhibits
robust antitumor efficacy in HRD tumors in vitro (CTG IC50 = 2.71 nM). Notably, SY-589 synergized strongly with
the PARP inhibitor Olaparib in vitro (Loewe score >20) and in vivo
(TGI = 109%), enhancing antitumor effects while permitting reduced
Olaparib dosing. Overall, SY-589 is a promising candidate
of Polθ inhibitor and has been positioned as a rational combination
partner with PARP inhibitors, aiming to overcome PARP inhibitor resistance
and mitigate their dose-limiting toxicities.