Evidence map›Paper›PMID 41850449›Full record

ArticleInternational journal of biological macromolecules2026

Chemical optimization of the exercise mimetic SLU-PP-332 enables insight into estrogen-related receptor signaling.

Hazem Essam Okda, Puhan Zhao, Matt Hayes, Colten Duvall, Elsa Quillin, Hong Fang, Bassem M Mohammed, Lamees Hegazy, Thomas P Burris, Bahaa Elgendy

Abstract read
In one paragraph

Article in International journal of biological macromolecules, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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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

10 authors.

Hazem Essam OkdaCenter for Clinical Pharmacology, Department of Anaesthesiology, Washington University in St. Louis, St. Louis, MO, 63110, United States.
Puhan ZhaoCenter for Clinical Pharmacology, Department of Anaesthesiology, Washington University in St. Louis, St. Louis, MO, 63110, United States.
Matt HayesDepartment of Cellular and Systems Pharmacology, University of Florida College of Pharmacy, Gainesville, FL, 32610, United States; University of Florida Genetics Institute, University of Florida School of Medicine, Gainesville, FL, 32610, United States.
Colten DuvallCenter for Clinical Pharmacology, Department of Anaesthesiology, Washington University in St. Louis, St. Louis, MO, 63110, United States; Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, MO, 63110, United States.
Elsa QuillinCenter for Clinical Pharmacology, Department of Anaesthesiology, Washington University in St. Louis, St. Louis, MO, 63110, United States.
Hong FangCenter for Clinical Pharmacology, Department of Anaesthesiology, Washington University in St. Louis, St. Louis, MO, 63110, United States; Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, MO, 63110, United States.
Bassem M MohammedEdward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, 63104, United States.
Lamees HegazyCenter for Clinical Pharmacology, Department of Anaesthesiology, Washington University in St. Louis, St. Louis, MO, 63110, United States; Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, MO, 63110, United States.
Thomas P BurrisDepartment of Cellular and Systems Pharmacology, University of Florida College of Pharmacy, Gainesville, FL, 32610, United States; University of Florida Genetics Institute, University of Florida School of Medicine, Gainesville, FL, 32610, United States.
Bahaa ElgendyCenter for Clinical Pharmacology, Department of Anaesthesiology, Washington University in St. Louis, St. Louis, MO, 63110, United States. Electronic address: belgendy@wustl.edu.

Funding

Exercise Mimetics for Dementia and Alzheimer's DiseaseRF1AG077160 · NIA · UNIVERSITY OF FLORIDA · PI BURRIS, THOMAS P, ELGENDY, BAHAA · 2023 to 2023
$2.3M
Exercise Mimetics for Dementia and Alzheimer's DiseaseR01AG077160 · NIA · UNIVERSITY OF FLORIDA · PI Thomas P Burris, Bahaa Elgendy · 2026 to 2026
$727k
Investigation and Targeting of Alternate Binding Site in ERRαR21DK132605 · NIDDK · ST. LOUIS COLLEGE OF PHARMACY · PI HEGAZY, LAMEES · 2022 to 2024
$574k
Development of Novel ERRa Selective Agonists as Chemical Probes for the Potential Treatment of Alzheimer's DiseaseR21AG065657 · NIA · ST. LOUIS COLLEGE OF PHARMACY · PI ELGENDY, BAHAA · 2020 to 2020
$427k
NIA NIH HHS R01 AG077160NIA NIH HHS R21 AG065657NIA NIH HHS RF1 AG077160NIDDK NIH HHS R21 DK132605
6 · The paper itself

Abstract

Estrogen-related receptors (ERRs) are master regulators of mitochondrial metabolism and exercise-responsive transcription, yet only a limited number of synthetic agonists with suitable potency and drug-like properties have been reported. SLU-PP-332 is a well-established exercise mimetic and widely used chemical probe for ERR activation; however, the structural features governing its potency, efficacy, selectivity, and drug-like properties have not been systematically elucidated. Here, we report the first comprehensive structure-activity relationship (SAR) analysis of the SLU-PP-332 scaffold, integrating chemical synthesis, cell-based functional assays, downstream gene-expression profiling, and computational modeling. Through iterative modification of core pharmacophoric elements, we identify key structural determinants that control ERRα and ERRγ agonism, transcriptional efficacy, ligand efficiency, and physicochemical properties. While SLU-PP-332 remains a strong benchmark for ERR activation, several analogues achieve comparable or context-dependent transcriptional responses while exhibiting improved ligand efficiency, solubility, or metabolic stability. Computational docking and molecular dynamics simulations reveal how subtle structural modifications influence ERR engagement and signaling outcomes. Together, this work defines design principles for tuning ERR agonism and provides a foundational SAR roadmap for the rational development of next-generation ERR agonists and exercise-mimetic therapeutics.

Indexed as

Receptors, EstrogenSignal TransductionERRalpha Estrogen-Related ReceptorHumansLigandsMolecular Docking SimulationMolecular Dynamics SimulationStructure-Activity RelationshipERRalpha Estrogen-Related ReceptorLigandsReceptors, EstrogenERR agonistsEstrogen-related receptors (ERRs)Exercise mimeticsSLU-PP-332Small-molecule modulatorsStructure–activity relationship (SAR)Transcriptional regulation

Identifiers

PMID41850449
PMCPMC13112601

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Registered trials

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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.