title: Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta.
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.
authors.affiliation: Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Gorczynski
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Zhou
authors.forename: Yali
authors.initials: Y
authors.lastname: Kong
authors.forename: Liya
authors.initials: L
authors.lastname: Roudaia
authors.forename: Michael G
authors.initials: MG
authors.lastname: Douvas
authors.forename: Miki
authors.initials: M
authors.lastname: Newman
authors.forename: Izabela
authors.initials: I
authors.lastname: Bielnicka
authors.forename: Gwen
authors.initials: G
authors.lastname: Baber
authors.forename: Takeshi
authors.initials: T
authors.lastname: Corpora
authors.forename: Jianxia
authors.initials: J
authors.lastname: Shi
authors.forename: Mohini
authors.initials: M
authors.lastname: Sridharan
authors.forename: Ryan
authors.initials: R
authors.lastname: Lilien
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Donald
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Speck
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: John H
authors.initials: JH
authors.lastname: Bushweller
mesh_terms: D000495:Allosteric Site; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D050658:Core Binding Factor beta Subunit / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D031541:Fluorescence Resonance Energy Transfer; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D009682:Magnetic Resonance Spectroscopy; D018995:Myosin Heavy Chains / Q000737:chemistry / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D024745:Smooth Muscle Myosins / Q000737:chemistry / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics / Q000502:physiology
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050658:Core Binding Factor beta Subunit; D004791:Enzyme Inhibitors; D011993:Recombinant Fusion Proteins; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains