Menin is a protein that directly interacts with the Mixed Lineage Leukemia 1 (MLL1) histone methyltransferase, and this protein-protein interaction (PPI) plays a critical role in various sub-types of acute leukemia with upregulated HOX genes. We developed first-in-class menin-MLL1 inhibitors, which specifically bind to menin at the MLL1 binding site. Using structure-based design combined with medicinal chemistry, we extensively optimized these compounds, which resulted in sub-nanomolar menin-MLL1 inhibitors with favorable drug-like properties. Our menin inhibitors demonstrate strong effect and specific mechanism of action in pre-clinical models of MLL1-rearranged and NPM1-mutated leukemia, including complete, long-lasting remission of leukemia. One of these compounds was introduced to clinical studies in AML patients by our licensing partner Kura Oncology and demonstrated encouraging clinical efficacy, resulting in recent transition to phase II clinical trials. Our work provides an example of successful targeting of PPIs with small molecules for new therapeutic applications. We also demonstrate how systematic structure-based optimization of PPI inhibitors can lead to in vivo active compounds and potentially new therapeutics.
Jolanta Grembecka, PhD, is a Professor in the Department of Pathology and Co-Leader of the Developmental Therapeutics Program in the Rogel Cancer Center at the University of Michigan. Dr. Grembecka's research has been focused on development of small molecule inhibitors of proteins involved in oncogenesis, with a particular focus on leukemia related proteins. Work from Dr. Grembecka's laboratory has been dedicated to develop small molecules targeting the protein-protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) as a new targeted therapy for acute leukemia patients with translocations of the MLL1 gene. Her laboratory has developed the first small molecule inhibitors of the menin-MLL1 interaction, which were licensed by Kura Oncology and advanced to phase II clinical trials in acute myeloid leukemia patients. Her laboratory is also pursuing development of new targeted therapies for hematologic and solid cancers by blocking novel epigenetic targets, including histone methyltransferases.
Dr. Grembecka received her
PhD in Chemistry at Wroclaw University of Technology, Poland. She
completed postdoctoral training in drug discovery at the University of
Virginia, before starting her independent laboratory at the University
of Michigan. Dr, Grembecka is a co-author on over 85 peer-reviewed
scientific publications and an inventor on 15 patents. She is a Leukemia
and Lymphoma Society Scholar and American Cancer Society Research