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

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• * DNA repair pathways are critical in cancer development and treatment resistance.
• * Homologous recombination (HR) deficiency creates vulnerabilities exploitable by targeting alternative repair mechanisms.
• * Polθ polymerase (Polθ-pol) is a key enzyme in microhomology-mediated end joining (MMEJ), implicated in HR-deficient cancers.

Purpose of the Study:

• * To discover and optimize novel small molecule inhibitors of Polθ-pol.
• * To evaluate the anti-cancer efficacy of these inhibitors in HR-deficient cancer models.
• * To assess the pharmacokinetic properties and in vivo efficacy of lead compounds.

Main Methods:

• * Synthesis and chemical optimization of an arylalkyne scaffold targeting Polθ-pol.
• * In vitro biochemical assays to determine Polθ-pol inhibitory activity (IC50).
• * In vitro antiproliferative assays against HR-deficient cancer cell lines (MDA-MB-436, Capan-1, DLD-1).
• * In vivo pharmacokinetic studies in mice and rats.
• * Xenograft tumor growth inhibition studies in an MDA-MB-436 model.

Main Results:

• * A novel series of Polθ-pol inhibitors with an arylalkyne scaffold was developed.
• * Compound 20 demonstrated potent Polθ-pol inhibition (IC50 = 1.3 nM) and significant antiproliferative effects on HR-deficient cancer cells.
• * Compound 20 exhibited excellent oral bioavailability (103.36% in mice, 63.71% in rats) and suppressed tumor growth in vivo with no evident toxicity.

Conclusions:

• * The arylalkyne scaffold is a highly effective strategy for developing potent Polθ-pol inhibitors.
• * Compound 20 represents a promising preclinical candidate for orally active Polθ-targeted cancer therapeutics.
• * Targeting Polθ-pol offers a viable therapeutic approach for HR-deficient cancers.