The Discovery of RP-2119: A Potent, Selective, and Orally Bioavailable Polθ ATPase Inhibitor

Area of Science:

• Molecular Biology
• Cancer Therapeutics
• Drug Discovery

Background:

• DNA polymerase theta (Polθ) is crucial for microhomology-mediated end joining (MMEJ) DNA repair.
• Polθ is a synthetic lethal target in cancers with homologous recombination (HR) deficiencies, particularly those with BRCA1/BRCA2 mutations.
• Inhibiting Polθ may synergize with PARP inhibitors in these cancers.

Purpose of the Study:

• To discover and develop RP-2119, a selective and potent Polθ ATPase inhibitor.
• To evaluate the preclinical efficacy and safety of RP-2119 in HR-deficient cancer models.
• To assess the synergistic potential of RP-2119 with olaparib in preclinical cancer models.

Main Methods:

• High-throughput ATPase screening and structural studies using cryo-electron microscopy (cryo-EM) to identify Polθ inhibitor binding sites.
• Lead optimization focusing on potency and ADME properties.
• In vitro cellular assays in HR-deficient cancer cell lines.
• In vivo studies using HR-deficient cell line and patient-derived mouse xenografts.

Main Results:

• Discovery of RP-2119, a selective, potent, and bioavailable Polθ ATPase inhibitor.
• RP-2119 demonstrated robust in vitro activity against HR-deficient cancer cell lines.
• RP-2119 showed significant synergy with olaparib in preclinical models of HR-deficient cancer.
• Combination therapy did not worsen hematological toxicity.

Conclusions:

• RP-2119 is a promising drug candidate for targeting Polθ in HR-deficient cancers.
• The combination of RP-2119 and olaparib represents a potential therapeutic strategy for BRCA-mutated cancers.
• RP-2119 exhibits a favorable preclinical profile for further clinical development.