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In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia
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In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia
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Journal Article
In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia
2024
Overview
Acute myeloid leukemia (AML) is fatal in the 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 performed
in-silico
screening of 212,966 compounds, selected 4 hits targeting the IQGAP1-GRD domain, and conducted SAR of the ‘fittest hit’ to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, resulted in G2/M arrest, and inhibited colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows response to IQGAP1 inhibition, and UR778Br, identified through
in-silico
studies, selectively targeted AML cells while sparing normal marrow.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/250
/ 631/67
/ 631/80
/ 692/4028
/ Animals
/ Antineoplastic Agents - pharmacology
/ Cell Proliferation - drug effects
/ Humanities and Social Sciences
/ Humans
/ Leukemia
/ Leukemia, Myeloid, Acute - drug therapy
/ Leukemia, Myeloid, Acute - genetics
/ Leukemia, Myeloid, Acute - metabolism
/ Leukemia, Myeloid, Acute - pathology
/ Lysates
/ mRNA
/ ras GTPase-Activating Proteins - antagonists & inhibitors
/ ras GTPase-Activating Proteins - genetics
/ ras GTPase-Activating Proteins - metabolism
/ Science
