Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta

Michael J Gorczynski; Jolanta Grembecka; Yunpeng Zhou; Yali Kong; Liya Roudaia; Michael G Douvas; Miki Newman; Izabela Bielnicka; Gwen Baber; Takeshi Corpora; Jianxia Shi; Mohini Sridharan; Ryan Lilien; Bruce R Donald; Nancy A Speck; Milton L Brown; John H Bushweller

doi:10.1016/j.chembiol.2007.09.006

Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta

Chem Biol. 2007 Oct;14(10):1186-97. doi: 10.1016/j.chembiol.2007.09.006.

Authors

Michael J Gorczynski¹, Jolanta Grembecka, Yunpeng Zhou, Yali Kong, Liya Roudaia, Michael G Douvas, Miki Newman, Izabela Bielnicka, Gwen Baber, Takeshi Corpora, Jianxia Shi, Mohini Sridharan, Ryan Lilien, Bruce R Donald, Nancy A Speck, Milton L Brown, John H Bushweller

Affiliation

¹ Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.

PMID: 17961830
DOI: 10.1016/j.chembiol.2007.09.006

Abstract

The two subunits of core binding factor (Runx1 and CBFbeta) play critical roles in hematopoiesis and are frequent targets of chromosomal translocations found in leukemia. The binding of the CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein to Runx1 is essential for leukemogenesis, making this a viable target for treatment. We have developed inhibitors with low micromolar affinity which effectively block binding of Runx1 to CBFbeta. NMR-based docking shows that these compounds bind to CBFbeta at a site displaced from the binding interface for Runx1, that is, these compounds function as allosteric inhibitors of this protein-protein interaction, a potentially generalizable approach. Treatment of the human leukemia cell line ME-1 with these compounds shows decreased proliferation, indicating these are good candidates for further development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Site*
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects*
Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors*
Core Binding Factor Alpha 2 Subunit / chemistry
Core Binding Factor Alpha 2 Subunit / metabolism
Core Binding Factor beta Subunit / antagonists & inhibitors*
Core Binding Factor beta Subunit / chemistry
Core Binding Factor beta Subunit / metabolism
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Fluorescence Resonance Energy Transfer
Hematopoiesis / genetics
Hematopoiesis / physiology
Humans
Leukemia / metabolism
Leukemia / pathology*
Magnetic Resonance Spectroscopy
Myosin Heavy Chains / chemistry
Myosin Heavy Chains / metabolism
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / metabolism
Smooth Muscle Myosins / chemistry
Smooth Muscle Myosins / metabolism
Translocation, Genetic / genetics
Translocation, Genetic / physiology

Substances

Core Binding Factor Alpha 2 Subunit
Core Binding Factor beta Subunit
Enzyme Inhibitors
Recombinant Fusion Proteins
Smooth Muscle Myosins
Myosin Heavy Chains