Mar 2023
Abstract:
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.
Bio:
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
Scholar.