Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta.
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.
Gorczynski
Michael J
MJ
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
Grembecka
Jolanta
J
Zhou
Yunpeng
Y
Kong
Yali
Y
Roudaia
Liya
L
Douvas
Michael G
MG
Newman
Miki
M
Bielnicka
Izabela
I
Baber
Gwen
G
Corpora
Takeshi
T
Shi
Jianxia
J
Sridharan
Mohini
M
Lilien
Ryan
R
Donald
Bruce R
BR
Speck
Nancy A
NA
Brown
Milton L
ML
Bushweller
John H
JH
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
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