The pharmacological profile of ART6043, a first-in-class clinical DNA polymerase theta polymerase domain inhibitor potentiating PARP inhibitor efficacy

DNA polymerase theta (Polθ ) is the central component of the DNA double strand break repair process of microhomology mediated end-joining (MMEJ). Targeting Polθ for cancer therapy has been proposed due to its tumour-selective expression, as well as its role in the survival of DNA damage response-defective cancer cells. Additionally, inhibition of Polθ has been shown to potentiate the effects of DNA damage induced by e.g. ionising radiation or poly(ADP-ribose) polymerase (PARP) inhibition. Here, we present the pharmacological profile of ART6043, a potent, selective, allosteric, small molecule inhibitor of the polymerase function of Polθ. We demonstrate that ART6043 inhibits Polθ with low nM potency and specifically abrogates MMEJ in cells. Consistent with this, ART6043 inhibits the survival of homologous recombination deficient (HRD) cells as monotherapy and potentiates the anti-tumour effects of PARP inhibitors in vitro. Furthermore, we demonstrate that ART6043 has excellent pharmaceutical properties, is well tolerated and induces tumour regressions in combination with PARP inhibitors in vivo in HRD models. The data demonstrate strong potential for ART6043 as an anti-cancer therapeutic for HRD tumours 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).