Discovery of Novel Orally Bioavailable Polθ Inhibitors with Arylalkyne Scaffolds for Targeting HR-Deficient Cancers

Polθ,
a key enzyme mediating microhomology-mediated end joining
(MMEJ), is overexpressed in multiple human cancers and represents
a promising therapeutic target, particularly in tumors with homologous
recombination (HR) deficiency. Herein, we report the discovery and
optimization of a novel series of Polθ polymerase (Polθ-pol)
inhibitors featuring an arylalkyne scaffold, which extends into a
peripheral channel within the polymerase domain to enhance target
engagement. Among the synthesized compounds, compound 20 exhibited potent inhibitory activity against Polθ-pol at a
nanomolar level (IC50 = 1.3 nM), along with antiproliferative
activity against the HR-deficient cancer cell lines, such as MDA-MB-436,
Capan-1, and DLD-1 (BRCA2–/–). Moreover,
compound 20 demonstrated favorable pharmacokinetic properties,
with oral bioavailability values of 103.36% in mice and 63.71% in
rats, respectively. In an MDA-MB-436 xenograft model, compound 20 significantly suppressed tumor growth without evident toxicity.
These findings underscore the arylalkyne scaffold as a highly promising
strategy for the development of orally active Polθ-targeted
therapeutics.