Paula Stefan, Jahani Farnaz, Almahmodi Dina, Sobota Sydni, Devaraja Shiffany, O'Brien Nicholas S, Young Kelly A, Prichard Kate, McCluskey Adam
Department of Chemistry, California State University Sacramento, 6000 J Street, Sacramento, CA, 95819, USA.
Chemistry, School of Environmental and Life Sciences, The University of Newcastle, University Drive, Callaghan, New South Wales, Australia.
ChemMedChem. 2025 Mar 3;20(5):e202400763. doi: 10.1002/cmdc.202400763. Epub 2024 Nov 21.
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.
肌浆网/内质网钙ATP酶（SERCA）的小分子变构激活剂有望成为操纵细胞内钙浓度的新型实验工具，以及治疗与胞质钙水平升高相关病症的治疗剂。在此，我们合成并表征了已知的SERCA变构激活剂CDN1163的20种类似物，并测试了它们刺激SERCA活性的能力。这些化合物的结构在母体支架醚部分的烷基以及含氮芳香环系统的组成上有所不同。活性最高的化合物表现出亚微摩尔范围内的效力，同时酶活性增加超过25%。观察到的构效关系表明，醚部分的庞大烷基以及喹啉环甲基取代基有利于活性。用嘧啶环系统取代喹啉会降低活性。为了构想一个潜在的机制，我们生成了SERCA在其催化循环的限速步骤中过渡态的分子模型。随后与CDN1163进行的盲对接确定了一个靠近酶ATP结合口袋的高亲和力结合位点，这表明激活剂可能通过帮助ATP结合和定位来加速SERCA的催化循环。
