Quinoline‐ and Pyrimidine‐based Allosteric Modulators of the Sarco/Endoplasmic Reticulum Calcium ATPase

Small-molecule allosteric activators of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA) hold promise as novel experimental tools to manipulate intracellular calcium concentrations and as therapeutic agents to treat medical conditions associated with elevated cytosolic calcium levels. Here, we synthesized and characterized 20 analogs of the known allosteric SERCA activator CDN1163 and tested their ability to stimulate SERCA activity. The structures of the compounds varied in the alkyl group of the parent scaffold's ether moiety as well as in the composition of the nitrogenous aromatic ring system. The most active compounds exhibited potencies in the sub-micromolar range while increasing enzyme activity by more than 25 %. The observed structure-activity relationships indicated that bulky alkyl groups in the ether moiety along with a quinoline ring methyl substituent were beneficial for activity. Replacement of the quinoline by a pyrimidine ring system reduced activity. To conceive a potential mechanism of action, we generated a molecular model of the transition state of SERCA when undergoing the rate-limiting step of its catalytic cycle. Subsequent blind docking with CDN1163 identified a high-affinity binding site close to the enzyme's ATP binding pocket, suggesting that the activators may accelerate SERCA's catalytic cycle by aiding in ATP binding and positioning.