Synthetic lethality (SL) is an innovative strategy in
targeted
anticancer therapy that exploits tumor genetic vulnerabilities. This
topic has come to the forefront in recent years, as witnessed by the
increased number of publications since 2007. The first proof of concept
for the effectiveness of SL was provided by the approval of poly(ADP-ribose)polymerase
inhibitors, which exploit a SL interaction in BRCA-deficient cells,
although their use is limited by resistance. Searching for additional
SL interactions involving BRCA mutations, the DNA polymerase theta
(POLθ) emerged as an exciting target. This review summarizes,
for the first time, the POLθ polymerase and helicase inhibitors
reported to date. Compounds are described focusing on chemical structure
and biological activity. With the aim to enable further drug discovery
efforts in interrogating POLθ as a target, we propose a plausible
pharmacophore model for POLθ-pol inhibitors and provide a structural
analysis of the known POLθ ligand binding sites.