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SAR-Guided Development of Small-Molecule SERCA2a Activators: Discovery of Potent Indoline, Benzofuran, and Benzodioxole Analogs for Cardiovascular Applications

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Název: SAR-Guided Development of Small-Molecule SERCA2a Activators: Discovery of Potent Indoline, Benzofuran, and Benzodioxole Analogs for Cardiovascular Applications
Autoři: Adam Ard, Carlos Cruz-Cortés, Xinmin Gan, Guadalupe Guerrero-Serna, Andrew D. White, Martin C. Clasby, L. Michel Espinoza-Fonseca
Rok vydání: 2025
Témata: Biophysics, Biochemistry, Medicine, Cell Biology, Pharmacology, Immunology, Science Policy, Chemical Sciences not elsewhere classified, three pharmacophoric regions, promising therapeutic target, natural product hits, limited structural data, 8 dual effectors, increasing atpase activity, serca2a stimulation occurs, drive serca2a activity, benzodioxole analogs emerged, 50 , 2 +, molecule serca2a activators, benzodioxole analogs, impaired activity, potent activators, molecule development, serca2a modulators, serca2a activation, pump serca2a, generation serca2a, ∼ 57, targeted therapies
Popis: Heart failure (HF) remains a major public health burden, with current therapies focused primarily on symptom management. Impaired activity of the cardiac Ca 2+ pump SERCA2a is a hallmark of HF and a promising therapeutic target, but limited structural data have hindered small-molecule development. Here, we report a comprehensive structure–activity relationship (SAR) investigation of small-molecule SERCA2a activators, beginning with natural product hits and progressing through iterative optimization of three pharmacophoric regions. This effort produced the largest collection of SERCA2a modulators to dateincluding 20 activators, 8 dual effectors, and 6 inhibitors. Several indoline, benzofuran, and benzodioxole analogs emerged as potent activators, increasing ATPase activity by ∼57% (EC 50 = 0.7–9 μM). Notably, SERCA2a activation was inversely correlated with Ca 2+ affinity, suggesting that SERCA2a stimulation occurs at the expense of Ca 2+ binding. In summary, these findings identify key structural features that drive SERCA2a activity and establish a framework for developing next-generation SERCA2a-targeted therapies.
Druh dokumentu: article in journal/newspaper
Jazyk: unknown
DOI: 10.1021/acs.jmedchem.5c01192.s001
Dostupnost: https://doi.org/10.1021/acs.jmedchem.5c01192.s001
https://figshare.com/articles/journal_contribution/SAR-Guided_Development_of_Small-Molecule_SERCA2a_Activators_Discovery_of_Potent_Indoline_Benzofuran_and_Benzodioxole_Analogs_for_Cardiovascular_Applications/29634101
Rights: CC BY-NC 4.0
Přístupové číslo: edsbas.3E1A42A7
Databáze: BASE
Popis
Abstrakt:Heart failure (HF) remains a major public health burden, with current therapies focused primarily on symptom management. Impaired activity of the cardiac Ca 2+ pump SERCA2a is a hallmark of HF and a promising therapeutic target, but limited structural data have hindered small-molecule development. Here, we report a comprehensive structure–activity relationship (SAR) investigation of small-molecule SERCA2a activators, beginning with natural product hits and progressing through iterative optimization of three pharmacophoric regions. This effort produced the largest collection of SERCA2a modulators to dateincluding 20 activators, 8 dual effectors, and 6 inhibitors. Several indoline, benzofuran, and benzodioxole analogs emerged as potent activators, increasing ATPase activity by ∼57% (EC 50 = 0.7–9 μM). Notably, SERCA2a activation was inversely correlated with Ca 2+ affinity, suggesting that SERCA2a stimulation occurs at the expense of Ca 2+ binding. In summary, these findings identify key structural features that drive SERCA2a activity and establish a framework for developing next-generation SERCA2a-targeted therapies.
DOI:10.1021/acs.jmedchem.5c01192.s001