Probing the Chemical Space of Polymerase Theta with Nucleotide Analogues Bearing a Stereogenic All-Carbon Quaternary Center

We
report findings on a novel family of nucleotide analogues with
selective inhibitory activity against DNA polymerase theta (Polθ),
a key enzyme in the theta-mediated end joining pathway and a critical
player in synthetic lethality-based cancer therapies. Polθ’s
intrinsically low fidelity, which contributes to genomic instability
in homologous recombination-deficient tumors, was probed for selective
targeting by these analogues. The newly identified compounds feature
an all-carbon stereogenic quaternary center at either the C3′
or C2′ position of the furanoside ring, a structural modification
that has already demonstrated potential in antiviral, anticancer,
and cardioprotective applications. Biochemical assays suggest these
analogues exploit Polθ’s unique active site architecture,
offering a possible direction for overcoming PARP inhibitor resistance
and enhancing personalized cancer treatment strategies.