Abstract LB459: BCCA7693 - A novel, orally bioavailable DNA-PK inhibitor demonstrates efficacy with targeted therapeutics by inhibiting the development of acquired resistance

Abstract Background: DNA-dependent protein kinase (DNA-PK), a key enzyme involved in non-homologous end joining (NHEJ) mediated DNA repair, is critical to cell survival following double strand break (DSB) inducing radio- and chemotherapy. Recently, DNA-PK has been implicated in driving the development of acquired resistance to molecular targeted therapeutics via repair of chromothripsis-induced DNA damage. In this study we report the development of BCCA7693, a novel, orally bioavailable DNA-PK inhibitor that emerged as the lead molecule from a rational, structure-based drug development program after synthesis and screening of 1000 novel structures in two distinct chemical classes. Methods: Biochemical and cellular assays were used to identify compounds having high potency, selectivity and desirable ADME characteristics. A novel multicellular spheroid screening assay was used to preselect for in vivo activity as well as extravascular distribution, a key parameter for the effectiveness of anticancer agents. Acquired resistance was evaluated both in vivo and in vitro via long-term continuous treatment regimens while monitoring growth rates and micronuclei formation. Results: BCCA7693 shows dose-dependent sensitization in xenograft-bearing murine models in combination with single and fractionated radiotherapy, exhibiting a sensitization enhancement factor of greater than 3-fold when BCCA7693 was administered in the diet at 75 mg/kg/day for two weeks following 5 Gy radiation. PK/PD and toxicity studies in mice, rats and dogs indicate characteristics suitable for clinical application with no hits in a 44-target safety screen panel. In mutated KRAS, BRAF and BRCA models, BCCA7693 demonstrated efficacy with targeted therapeutics, decreasing tumour cell survival during replicative stress and blocking the development of acquired resistance with trametinib, adagrasib, dabrafenib, afatinib, olaparib and the pol-θ inhibitor ART558. In Colo-205 xenografts (BRAF V600E mut) we demonstrate complete tumour control for 8 weeks with continuous trametinib + dabrafenib + BCCA7693 treatment via diet (0. 1, 10 and 75 mg/kg/day respectively) compared to disease progression at week 3 for trametinib + dabrafenib alone. Conclusions: In contrast to conventional DSB inducing radio- and chemotherapy, murine studies with BCCA7693 did not result in increased toxicity/weight loss for combination treatments with the molecular targeted therapeutics, suggesting the potential for an additional clinical application of this DSB repair inhibitor. BCCA7693, shows potential for combination with a range of targeted cancer therapeutics. Citation Format: Alastair H. Kyle, Judit P. Banath, Sevin Teymori, Ela Smiljanic-Hurley, Simon Osborne, Jay Paquette, Steve Arns, Claudio Sturino, Joseph Mancini, Andrew I. Minchinton. BCCA7693 - A novel, orally bioavailable DNA-PK inhibitor demonstrates efficacy with targeted therapeutics by inhibiting the development of acquired resistance abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB459.