Evidence map›Paper›PMID 38712210›Full record

ArticlebioRxiv : the preprint server for biology2024

Development of Allosteric Small Molecule APOBEC3B Inhibitors from

Katherine F M Jones, Özlem Demir, Mackenzie K Wyllie, Michael J Grillo, Clare Morris, Sophia P Hirakis, Rahul Dadabhau Kardile, Michael A Walters, Reuben S Harris, Rommie E Amaro and 1 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

11 authors.

Katherine F M JonesDepartment of Chemistry, University of Minnesota, Minneapolis, MN, USA.
Özlem DemirDepartment of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.
Mackenzie K WyllieDepartment of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
Michael J GrilloDepartment of Chemistry, University of Minnesota, Minneapolis, MN, USA.
Clare MorrisDepartment of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.
Sophia P HirakisDepartment of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.
Rahul Dadabhau KardileDepartment of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
Michael A WaltersDepartment of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
Reuben S HarrisDepartment of Biochemistry & Structural Biology, University of Texas Health Science Center San Antonio, San Antonio, TX, USA.
Rommie E AmaroDepartment of Chemistry and Biochemistry, University of California - San Diego, La Jolla, CA, USA.ORCID 0000-0002-9275-9553
Daniel A HarkiDepartment of Chemistry, University of Minnesota, Minneapolis, MN, USA.ORCID 0000-0001-5950-931X

Funding

PROJECT 3 – BIOLOGY OF DNA DEAMINASES IN CANCERP01CA234228 · NCI · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI Michael Allen Carpenter · 2019 to 2026
$14.5M
Contemporary Approaches to Cancer Cell Signaling and CommunicationT32CA009523 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI DONOGHUE, DANIEL J, YANG, JING · 1985 to 2025
$12.1M
NCI NIH HHS P01 CA234228NCI NIH HHS T32 CA009523
6 · The paper itself

Abstract

APOBEC3B cytosine deaminase contributes to the mutational burdens of tumors, resulting in tumor progression and therapy resistance. Small molecule APOBEC3B inhibitors have potential to slow or mitigate these detrimental outcomes. Through molecular dynamics (MD) simulations and computational solvent mapping analysis, we identified a novel putative allosteric pocket on the C-terminal domain of APOBEC3B (A3Bctd), and virtually screened the ChemBridge Diversity Set (N~110,000) against both the active and potential allosteric sites. Selected high-scoring compounds were subsequently purchased, characterized for purity and composition, and tested in biochemical assays, which yielded 13 hit compounds. Orthogonal NMR assays verified binding to the target protein. Initial selectivity studies suggest these compounds preferentially target A3Bctd over related deaminase APOBEC3A (A3A), and MD simulations indicate this selectivity may be due to the steric repulsion from H56 that is unique to A3A. Taken together, our studies represent the first virtual screening effort against A3Bctd that has yielded candidate inhibitors suitable for further development.

Identifiers

PMID38712210
PMCPMC11071470

What OpenQuestion holds

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Registered trials

None linked

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.