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

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.