Evidence map›Paper›PMID 38834690›Full record

ArticleScientific reports2024

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

Deepak M Sahasrabudhe, Jane L Liesveld, Mohammad Minhajuddin, Niloy A Singh, Subhangi Nath, Vishuwes Muthu Kumar, Marlene Balys, Andrew G Evans, Mitra Azadniv, Jeanne N Hansen and 7 more

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In one paragraph

Article in Scientific reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Deepak M Sahasrabudhe *Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY, 14618, USA. Deepak_Sahasrabudhe@urmc.rochester.edu.
Jane L LiesveldWilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY, 14618, USA.
Mohammad MinhajuddinDivision of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, US.
Niloy A SinghDepartment of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA.
Subhangi NathDepartment of Chemistry, Birla Institute of Technology, Ranchi, Jharkhand, India.
Vishuwes Muthu KumarDepartment of Chemistry, Birla Institute of Technology, Ranchi, Jharkhand, India.
Marlene BalysGenomics Research Center, University of Rochester Medical Center, Rochester, NY, USA.
Andrew G EvansDepartment of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Mitra AzadnivDepartment of Medicine, Hematology/Oncology, University of Rochester Medical Center, Rochester, NY, USA.
Jeanne N HansenDepartment of Psychological and Brain Sciences, Colgate University, Hamilton, NY, USA.
Michael W BeckerIndiana University School of Medicine, Indianapolis, IN, USA.
Ashoke SharonDepartment of Chemistry, Birla Institute of Technology, Ranchi, Jharkhand, India.
V Kaye ThomasDepartment of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Richard G MooreDivision of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA.
Manoj K KheraPresude Lifesciences Pvt Ltd., Uttam Nagar, New Delhi, 110059, India.
Craig T JordanDivision of Hematology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, US.
Rakesh K Singh *Division of Obstetrics and Gynecology, University of Rochester Medical Center, Rochester, NY, USA. Rakesh_Singh@urmc.rochester.edu.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Cell ProliferationLeukemia, Myeloid, Acuteras GTPase-Activating ProteinsAnimalsAntineoplastic AgentsApoptosisCell Line, TumorComputer SimulationHumansProtein DomainsProteomicsAntineoplastic AgentsIQ motif containing GTPase activating protein 1ras GTPase-Activating Proteins

Identifiers

PMID38834690
PMCPMC11150481

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.