SAR-Guided Development of Small-Molecule SERCA2a Activators: Discovery of Potent Indoline, Benzofuran, and...

Heart failure (HF) remains a major public health burden, with current therapies focused primarily on symptom management. Impaired activity of the cardiac Ca²⁺ 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% (EC₅₀ = 0.7-9 μM). Notably, SERCA2a activation was inversely correlated with Ca²⁺ affinity, suggesting that SERCA2a stimulation occurs at the expense of Ca²⁺ binding. In summary, these findings identify key structural features that drive SERCA2a activity and establish a framework for developing next-generation SERCA2a-targeted therapies.