The NIH's Illuminating the Druggable Genome (IDG) project promotes investigation of historically understudied kinases. To aid in target validation efforts and further study biological and molecular roles of these kinases, selective and potent molecular probes must be discovered and developed. BUB1B is one such kinase which does not have known molecular probe compounds which satisfy the activity threshold of < 30nM (referred to as target development level (TDL), Tbio). BUB1B was identified as a kinase of interest in a pan-cancer genomic, transcriptomic, pathologic and clinical study of all kinases in The Cancer Genome Atlas (TCGA). Our work shows that BUB1B is overexpressed in 19 solid-tumors and that its increased mRNA levels correlate with negative clinical outcomes including overall survival and TNM staging. BUB1B plays a role in mitotic checkpoints and interacts closely with the cancer target AURKB at the anaphase promoting complex. Using a combination of computational methods including homology modeling, machine learning, and extended molecular dynamics simulations, three BUB1B homology models were utilized for high-throughput docking. Three compound libraries were also resourced for potential small molecule inhibitors for BUB1B. By filtering for compounds with lead-like properties, ~5,000 compounds were selected for future high-throughput docking studies. Future work includes preparing the compounds for docking. Ultimately, these compounds will be scored and rank-ordered to obtain highest performing compounds. The best performing compounds will then be purchased for in-vitro experiments, with the goal of successfully identifying a small molecule kinase inhibitor for the understudied BUB1B kinase.
