2. Academic Validation
  3. In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia

In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia

  • Sci Rep. 2024 Jun 4;14(1):12868. doi: 10.1038/s41598-024-63392-2.
Deepak M Sahasrabudhe # 1 2,  Jane L Liesveld 3 4,  Mohammad Minhajuddin 5,  Niloy A Singh 4,  Subhangi Nath 6,  Vishuwes Muthu Kumar 6,  Marlene Balys 7,  Andrew G Evans 8,  Mitra Azadniv 4,  Jeanne N Hansen 9,  Michael W Becker 10,  Ashoke Sharon 6,  V Kaye Thomas 11,  Richard G Moore 12,  Manoj K Khera 13,  Craig T Jordan 5,  Rakesh K Singh # 14 15
Affiliations

Affiliations

  • 1 Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY, 14618, USA. [email protected].
  • 2 Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA. [email protected].
  • 3 Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY, 14618, USA.
  • 4 Department of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA.
  • 5 Division of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, US.
  • 6 Department of Chemistry, Birla Institute of Technology, Ranchi, Jharkhand, India.
  • 7 Genomics Research Center, University of Rochester Medical Center, Rochester, NY, USA.
  • 8 Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
  • 9 Department of Psychological and Brain Sciences, Colgate University, Hamilton, NY, USA.
  • 10 Indiana University School of Medicine, Indianapolis, IN, USA.
  • 11 Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
  • 12 Division of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA.
  • 13 Presude Lifesciences Pvt Ltd., Uttam Nagar, New Delhi, 110059, India.
  • 14 Division of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA. [email protected].
  • 15 Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA. [email protected].
  • # Contributed equally.
PMID: 38834690 DOI: 10.1038/s41598-024-63392-2
Abstract

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-163707
    IQGAP1 Inhibitor