The Pharmacologic Profile of ART6043, a First-in-Class Clinical DNA Polymerase Theta Polymerase Domain Inhibitor Potentiating PARP Inhibitor Efficacy

Abstract Purpose: DNA polymerase theta (Polθ) is the central component of DNA double-strand break repair through microhomology-mediated end joining (MMEJ). Targeting Polθ for cancer therapy has been proposed due to its tumor-selective expression, as well as its role in the survival of homologous recombination–deficient (HRD) cancer cells. Additionally, inhibition of Polθ has been shown to potentiate the effects of DNA damage, such as that caused by poly (ADP-ribose) polymerase (PARP) inhibition. In this study, we present the pharmacologic profile of ART6043, a potent, selective, allosteric, small-molecule inhibitor of the polymerase function of Polθ. Experimental Design: A series of in vitro studies were performed to demonstrate the biochemical and cellular on-target activity of ART6043 in relevant model systems, focusing on combination with PARP inhibitors. Subsequent in vivo studies established a pharmacokinetic/pharmacodynamic/efficacy relationship and explored ART6043’s ability to potentiate the efficacy of PARP inhibitors across a range of cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and genetically engineered mouse models of HRD tumors. Results: ART6043 inhibits Polθ with low nmol/L potency and specifically abrogates MMEJ in cells. Additionally, ART6043 inhibits the survival of HRD cells and potentiates the efficacy of PARP inhibitors in vitro. Furthermore, ART6043 has excellent pharmaceutical properties, is well tolerated, and induces tumor regressions in combination with PARP inhibitors in vivo in HRD models. Conclusions: The data demonstrate strong potential for ART6043 as an anticancer therapeutic for HRD tumors in combination with PARP inhibitors. Based on this, combination therapy of ART6043 with PARP inhibitor treatment is being tested in an ongoing phase I/IIa clinical trial (NCT05898399).