Poster Presentation Royal Australian Chemical Institute National Congress 2026

Novel Treatment of Heart Disease - Activators of SERCA2a  (#422)

Christopher CA Anderson 1 2 3 4
  1. University of Newcastle, Callaghan, NSW, Australia
  2. University of Newcastle, Adam McCluskey , Newcastle, NSW, Australia
  3. University of Sacramento , Stefan Paula , Sacramento, California, USA
  4. University of Newcastle, Nicholas O'brien, Newcastle, NSW, Australia

Sarco/Endoplasmic Reticulum Calcium-ATPase (SERCA) is a family of enzymes found in all muscle cells within the body. SERCA plays a critical role in modulating the calcium cycle. A Ca2+ influx into cells and binding to the sarcomere, massively increases the localised Ca2+ triggering muscle contraction. SERCA removes this Ca2+, acting as a pump to return calcium ions into storage in the sarcoplasmic reticulum, with concomitant muscle relaxation.

In the heart, this cycle translates to the maintenance of normal cardiac function. Failing or poorly expressed SERCA leads to a disruption in the cardiac cycle, with dire consequences including heart disease and death 1. Activation of SERCA by small molecule activators has the potential to restore the calcium cycle and normal heart function 2.

Several small molecule activators of SERCA have been reported in the literature 3, these compounds have the potential to restore SERCA activity to alleviate heart failure. Our group has previously focussed on one of these activators, CDN1163, creating analogue libraries and exploring their binding modes, as well as their activity towards SERCA 2.  Utilising molecular docking and structure activity relationship (SAR) tables, we have developed a further library of compounds, seeking to create new SERCA activators as novel treatments of heart disease.

  1. 1. Zhihao, L.; Jingyu, N.; Lan, L.; Michael, S.; Rui, G.; Xiyun, B.; Xiaozhi, L.; Guanwei, F. SERCA2a: A Key Protein in the Ca2+ Cycle of the Heart Failure. Heart Fail Rev 2020, 25 (3), 523–535. https://doi.org/10.1007/s10741-019-09873-3.
  2. 2. Paula, S.; Jahani, F.; Almahmodi, D.; Sobota, S.; Devaraja, S.; O’Brien, N. S.; Young, K. A.; Prichard, K.; McCluskey, A. Quinoline‐ and Pyrimidine‐based Allosteric Modulators of the Sarco/Endoplasmic Reticulum Calcium ATPase. ChemMedChem 2025, 20 (5), e202400763. https://doi.org/10.1002/cmdc.202400763.
  3. 3. Cornea, R. L.; Gruber, S. J.; Lockamy, E. L.; Muretta, J. M.; Jin, D.; Chen, J.; Dahl, R.; Bartfai, T.; Zsebo, K. M.; Gillispie, G. D.; Thomas, D. D. High-Throughput FRET Assay Yields Allosteric SERCA Activators. SLAS Discovery 2013, 18 (1), 97–107. https://doi.org/10.1177/1087057112456878.