Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure

Luraghi, Andrea; Ferrandi, Mara; Barassi, Paolo; Arici, Martina; Hsu, Shih‐Che; Torre, Eleonora; Ronchi, Carlotta; Romerio, Alessio; Chang, Gwo‐Jyh; Ferrari, Paolo; Bianchi, Giuseppe; Zaza, Antonio; Rocchetti, Marcella; Peri, Francesco

doi:10.1021/acs.jmedchem.2c00347

Cited by 13 publications

(29 citation statements)

References 28 publications

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“…Of all these SERCA2a activators only istaroxime, a known Na + /K + transporting ATPase inhibitor as well as an inotropic/lusitropic agent acting to enhance SERCA2a activity, has been in phase IIb clinical trials for treatment of heart failure 45,46 . However, because of its unsuitability for human usage (poor gastrointestinal absorption, high clearance rate, and extensive metabolic transformation) 46 , istaroxime derivatives were designed from QSAR studies and a new promising class of SERCA2a activators has been identi ed 47,48,49 .…”

Section: Discussionmentioning

confidence: 99%

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

Roopnarine

Yuen

Thompson

et al. 2023

Preprint

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We have used FRET-based biosensors in live cells, in a robust high-throughput screening (HTS) platform, to identify small-molecules that alter the structure and activity of the cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA2a). Our primary aim is to discover drug-like small-molecule activators that improve SERCA’s function for the treatment of heart failure. We have previously demonstrated the use of an intramolecular FRET biosensor, based on human SERCA2a, by screening a small validation library using novel microplate readers that can detect the fluorescence lifetime or emission spectrum with high speed, precision, and resolution. Here we report results from a 50,000-compound screen using the same biosensor, with hit compounds functionally evaluated using Ca2+-ATPase and Ca2+-transport assays. We focused on 18 hit compounds, from which we identified eight structurally unique compounds and four compound classes as SERCA modulators, approximately half of which are activators and half are inhibitors. While both activators and inhibitors have therapeutic potential, the activators establish the basis for future testing in heart disease models and lead development, toward pharmaceutical therapy for heart failure.

show abstract

Section: Discussionmentioning

confidence: 99%

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

Roopnarine

Yuen

Thompson

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

Roopnarine

Yuen

Thompson

et al. 2023

Preprint

View full text Add to dashboard Cite

We have used FRET-based biosensors in live cells, in a robust high-throughput screening (HTS) platform, to identify small-molecules that alter the structure and activity of the cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA2a). Our primary aim is to discover drug-like small-molecule activators that improve SERCA's function for the treatment of heart failure. We have previously demonstrated the use of an intramolecular FRET biosensor, based on human SERCA2a, by screening a small validation library using novel microplate readers that can detect the fluorescence lifetime or emission spectrum with high speed, precision, and resolution. Here we report results from a 50,000-compound screen using the same biosensor, with hit compounds functionally evaluated using Ca2+-ATPase and Ca2+-transport assays. We focused on 18 hit compounds, from which we identified eight structurally unique compounds and four compound classes as SERCA modulators, approximately half of which are activators and half are inhibitors. While both activators and inhibitors have therapeutic potential, the activators establish the basis for future testing in heart disease models and lead development, toward pharmaceutical therapy for heart failure.

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“…The enhancement of SR calcium load can be achieved by SERCA2a overexpression or by modification of signaling cascades that regulate SERCA2a at multiple levels, for example, via displacement or attenuating the inhibitory effect of the small endogenous protein phospholamban (PLB). ,− Recently, Luraghi et al reported on selective SERCA2a activators, derivatives of istaroxime metabolite, with unknown mechanism of action . There are published data on the N -aryl- N -alkyl-thiophene-2-carboxamide compound, which increases endoplasmic reticulum Ca 2+ load by enhancing SERCA2a-mediated Ca 2+ transport .…”

Section: Introductionmentioning

confidence: 99%

1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities

Mitronova,

Quentin,

Belov

et al. 2023

J. Med. Chem.

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To discover new multifunctional agents for the treatment of cardiovascular diseases, we designed and synthesized a series of compounds with a cyclopropyl alcohol moiety and evaluated them in biochemical assays. Biological screening identified derivatives with dual activity: preventing Ca 2+ leak through ryanodine receptor 2 (RyR2) and enhancing cardiac sarco-endoplasmic reticulum (SR) Ca 2+ load by activation of Ca 2+ -dependent ATPase 2a (SERCA2a). The compounds that stabilize RyR2 at micro- and nanomolar concentrations are either structurally related to RyR-stabilizing drugs or Rycals or have structures similar to them. The novel compounds also demonstrate a good ability to increase ATP hydrolysis mediated by SERCA2a activity in cardiac microsomes, e.g., the half-maximal effective concentration (EC 50 ) was as low as 383 nM for compound 12a, which is 1,4-benzothiazepine with two cyclopropanol groups. Our findings indicate that these derivatives can be considered as new lead compounds to improve cardiac function in heart failure.

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Highly Selective SERCA2a Activators: Preclinical Development of a Congeneric Group of First-in-Class Drug Leads against Heart Failure

Cited by 13 publications

References 28 publications

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators

1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities

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