Abstract A093: Potential combination partners for a novel CDC7-selective Inhibitor, TAK-931

Background: Cell division cycle 7 (CDC7) is a serine/threonine kinase, which plays important roles in initiation of DNA replication. We developed a CDC7-selective inhibitor, TAK-931, designed to inhibit CDC7 activity in a time-dependent and ATP-competitive manner. In this study, we aimed to identify potential combination partners for TAK-931 to guide clinical combination strategies. Methods: In vitro combination studies of various agents with TAK-931 were carried out in COLO205, A549, SW620, SW48, H460, and HCT116 cancer cells using a fully automated system for assay execution and data analysis (Double Agent studies). Agents tested in combination with TAK-931 included: DNA damaging agents, tubulin binders, mitosis inhibitors, cell signaling modulators, proteasome inhibitors, and other targeted agents with significant single-agent activity against these cell lines. Treated stable isotope labeling using amino acids in cell culture (SILAC)-labeled H460 cells were subjected to quantitative mass spectrometry. In vivo combination studies of TAK-931 using DNA damaging agents or IR were conducted in multiple human xenograft models including patient-derived xenograft models (PDXs). Results: The Double Agent studies revealed that DNA damaging agents, such as topoisomerase inhibitors and platinum compounds, had the highest occurrence of synergistic antiproliferative effects in combination with TAK-931. In the phosphoproteomics analysis, gene ontology (GO) enrichment analysis revealed that DNA repair (p Citation Format: Kenichi Iwai, Kurt Eng, Tadahiro Nambu, Jie Yu, Masamitsu Gotou, Sakiyo Tsukamoto, Saomi Murai, Shun-Ichiro Kageyama, Yukie Kashima, Susumu Kobayashi, Akihiro Ohashi. Potential combination partners for a novel CDC7-selective Inhibitor, TAK-931 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A093. doi:10.1158/1535-7163.TARG-19-A093