Abstract 5161: Validation of drug candidates targeting dormant cancers in live cells as a key for successful translation into the clinic

Abstract

Abstract Thermal shift assay was utilized to demonstrate target engagement of drug candidate compounds to their specific targets. We explored novel cancer dormancy targets: DYRK1B and AXL kinases and assessed interaction with corresponding small molecule inhibitors. We demonstrated the correlation of direct target binding with ASMS (affinity selected mass spectrometry) and mechanism of action with cell-based phenotypic assays (using flow cytometry) for previously identified and current clinical candidates. We demonstrated that the above described approach can characterize and potentially predict clinical activity of novel molecules. Herein we investigated DYRK1B inhibitors from an azaindole-quinoline series. It was shown earlier that these molecules have picomolar activity in in vitro assays against DYRK1 kinases (DYRK1B and DYRK1A) and now we confirmed their DYRK1B specificity in cells as well as their activity against dormant cancers. We suggest that described inhibitors are valid clinical candidates for targeting cancer dormancy based on direct target binding and engagement in live cancer cells. These compounds in combination with chemotherapeutic agents, have the potential to improve patient outcomes and prolong survival. Citation Format: Alexei Belenky, Alexandra Kuznetsova, Michael Frid, Felix Chapovsky, Marc Duey, Maria Vilenchik. Validation of drug candidates targeting dormant cancers in live cells as a key for successful translation into the clinic [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5161.