Affiliation:
1. University of Rochester Medical Center
2. University of Colorado Anschutz Medical Campus
3. Birla Institute of Technology
4. Colgate University
5. University of Rochester
6. Presude Lifesciences Pvt Ltd
Abstract
AbstractAcute myeloid leukemia (AML) is fatal in majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performedin-silicoscreening of 212,966 compounds, selected 4 hits targeting IQGAP1-GRD domain, and conducted SAR of ‘fittest hit’ to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, G2/M arrest, and colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. IQGAP1/F-actin showed co-localization and UR778Br induced filopodia formation in U937 cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows dependency on IQGAP1 and UR778Br, identified throughin-silicostudies, selectively targeted AML cells while sparing normal marrow.
Publisher
Research Square Platform LLC
Reference63 articles.
1. Acute myeloid leukemia;Döhner H;N. Eng. J. of Med.,2015
2. Segel, R., Miller, K., Fuchs H and Jemal A. Cancer Statistics, CA: A Journal for Clinicians 71, 7–33 (2021).
3. Current management of childhood acute myeloid leukemia;Rubnitz JE;Paed. Drugs,2017
4. Patterns of care and survival for elderly acute myeloid leukemia-challenges and opportunities;Mangaonkar AA;Curr. Hematol. Malig. Rep,2017
5. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry;Juliusson G;Blood,2009