Abstract
The majority of chronic myeloid leukemia (CML) cases are caused by a chromosomal translocation linking the breakpoint cluster region (BCR) gene to the Abelson murine leukemia viral oncogene-1 (ABL1), creating the mutant fusion protein BCR-ABL1. Downstream of BCR-ABL1 is growth factor receptor-bound protein-2 (GRB2), an intracellular adapter protein that binds to BCR-ABL1 via its src-homology-2 (SH2) domain. This binding constitutively activates growth pathways, downregulates apoptosis, and leads to an over proliferation of immature and dysfunctional myeloid cells. Utilizing novel synthetic methods, we developed four furo-quinoxaline compounds as GRB2 SH2 domain antagonists with the goal of disrupting this leukemogenic signaling. One of the four antagonists, NHD2-15, showed a significant reduction in proliferation of K562 cells, a human BCR-ABL1+ leukemic cell line. To elucidate the mode of action of these compounds, various biophysical, in vitro, and in vivo assays were performed. Surface plasmon resonance (SPR) assays indicated that NHD2-15 antagonized GRB2, binding with a KD value of 119 ± 2 μM. Cellulose nitrate (CN) assays indicated that the compound selectively bound the SH2 domain of GRB2. Western blot assays suggested the antagonist downregulated proteins involved in leukemic transformation. Finally, NHD2-15 was nontoxic to primary cells and adult zebrafish, indicating that it may be an effective clinical treatment for CML.
Highlights
Myeloid cells are leukocytes whose major role is to destroy pathogens invading the body
hematopoietic stem cell (HSC) that generate myeloid cells first differentiate into a common myeloid progenitor (CMP) [4, 5], which is capable of generating other hematopoietic progenitor cell (HPC) types called megakaryocyte
NHD2-15 bound to the SH2 domains of growth factor receptor-bound protein-2 (GRB2) when analyzed by a Cellulose nitrate (CN) binding assay
Summary
Myeloid cells are leukocytes whose major role is to destroy pathogens invading the body. All mature blood cells, including myeloid cells, originate from a multipotent hematopoietic stem cell (HSC) that must generate blood cells for an organism’s lifespan [1,2,3]. HSCs that generate myeloid cells first differentiate into a common myeloid progenitor (CMP) [4, 5], which is capable of generating other hematopoietic progenitor cell (HPC) types called megakaryocyte-.
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