Mar 2023
Abstract:
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.
Bio:
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.