Evidence mapPaperPMID 40216016Full record

ReviewJournal of molecular biology2025

Resistance to Allosteric Inhibitors.

Ian R Outhwaite, Isabelle Kwan, Ariel Leyte-Vidal, Neil P Shah, Ivet Bahar, Markus A Seeliger

Abstract readReview
In one paragraph

Review in Journal of molecular biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

4 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. 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

6 authors.

Ian R OuthwaiteDepartment of Pharmacological Sciences, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Isabelle KwanLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA.
Ariel Leyte-VidalDepartment of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33101, USA; Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA 94143, USA.
Neil P ShahDivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA 94143, USA.
Ivet BaharLaufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biochemistry and Cell Biology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
Markus A SeeligerDepartment of Pharmacological Sciences, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Laufer Center for Physical and Quantitative Biology, Stony Brook University, Stony Brook, NY 11794, USA. Electronic address: markus.seeliger@stonybrook.edu.

Funding

MEDICAL SCIENTIST TRAINING PROGRAMT32GM008444 · NIGMS · STATE UNIVERSITY NEW YORK STONY BROOK · PI FROHMAN, MICHAEL A. · 1992 to 2024
$12.6M
Dynamics of Ligand Binding and Protein Kinase Regulation_RenewalR35GM119437 · NIGMS · STATE UNIVERSITY NEW YORK STONY BROOK · PI Markus A Seeliger · 2016 to 2026
$6.5M
Chemical Biology Training InterfaceT32GM136572 · NIGMS · STATE UNIVERSITY NEW YORK STONY BROOK · PI ELIZABETH M BOON, Jessica Chuang Seeliger · 2020 to 2026
$2.9M
Toward a Deeper Understanding of Allostery and Allotargeting by Computational ApproachesR01GM139297 · NIGMS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Ivet Bahar · 2021 to 2026
$2.8M
Maximizing Selective Inhibition of Clinically Observed MET MutantsF30CA281272 · NCI · STATE UNIVERSITY NEW YORK STONY BROOK · PI Ian Outhwaite · 2024 to 2026
$151k
NCI NIH HHS F30 CA281272NIGMS NIH HHS R01 GM139297NIGMS NIH HHS R35 GM119437NIGMS NIH HHS T32 GM008444NIGMS NIH HHS T32 GM136572
6 · The paper itself

Abstract

Allosteric inhibitors have emerged as powerful therapeutic agents capable of overcoming resistance mutations that impair the efficacy of orthosteric inhibitors. However, resistance to allosteric inhibitors can also arise, posing a challenge to their long-term effectiveness. Mechanisms of resistance include altered inhibitor affinity and kinetics, disruption of the allosteric mechanism, changes in receptor recycling and activity, and off-target adaptations such as upregulation of drug efflux pumps or activation of compensatory signaling pathways. Furthermore, the specific mechanism of allosteric regulation induced by inhibitor binding can itself be susceptible to resistance mutations, leading to diminished efficacy. Understanding these diverse resistance mechanisms is crucial for developing strategies to counteract them. One promising approach involves the combination of both allosteric and orthosteric inhibitors, either as separate agents or as linked "bitopic" compounds, to mitigate the impact of resistance mutations. This review explores the molecular basis of resistance to allosteric inhibitors and potential strategies to overcome resistance, offering insights for the development of more resilient therapies.

Indexed as

Drug ResistanceAllosteric RegulationAnimalsHumansMutationSignal Transductionallosterydrug resistanceenzymemechanism

Identifiers

PMID40216016
PMCPMC12926998

What Socratic holds

Textmetadata
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Read underepoch 390

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 Socratic graph.