Development of small molecule inhibitors for novel proteins and proteins lacking well defined binding sites remains a challenging task. One of the efficient methods is based on screening of a large number of drug-like molecules using biochemical assays. However, this requires significant resources and access to a large panel of diverse and high quality compound libraries. Fragment-based lead discovery (FBLD) represents an alternative and unique approach that overcomes limitation of high-throughput screening. It allows for unbiased identification of small molecule ligands binding to both orthosteric and allosteric protein sites. Initial hits have typically low affinity and require extensive medicinal chemistry optimization. FBLD can be successfully applied to novel and unexplored proteins and can generate new chemical scaffolds with optimized drug-like properties. Efficient application of FBLD requires a combination of very sensitive screening techniques, high quality fragment library and extensive use of structural biology. We have applied FBLD approach to target several challenging proteins, including histone methyltransferases ASH1L and NSD1 as well as ubiquitin ligase RING1B. As a result, we have developed first-in-class small molecule inhibitors of these proteins with biological activity in cancer models. These small molecules represent valuable lead compounds for more advanced drug discovery campaigns.
Dr. Cierpicki is a Professor in the Department of Pathology at the University of Michigan. He received MSc in chemistry from the Department of Chemistry, Wrocław University of Technology in Poland and PhD in biochemistry from the Department of Biochemistry and Molecular Biology; University of Wrocław in Poland. He joined the Department of Pathology at the University of Michigan in 2009 and his research interest is in the area of chemical biology and cancer epigenetics. His laboratory has developed first-in-class inhibitors of the menin-MLL interaction as a new potential therapeutic strategy in MLL leukemias. His current efforts are focused on development of small molecule inhibitors targeting cancer related epigenetic proteins, such as PRC1, NSD and ASH1L histone methyltransferases, GAS41.
Dr. Cierpicki is a co-author of over 100 peer-reviewed scientific publications and an inventor on over 8 patents. He is a Leukemia and Lymphoma Society Scholar, American Cancer Society Research Scholar, Senior Forbes Institute Scholar and Rogel Scholar.