Combination of The CRAC Channel Inhibitor CM4620 And Galactose as A Potential Therapy for Acute Pancreatitis

Function Pub Date : 2024-04-05 DOI:10.1093/function/zqae017
S. Lewis, D. Evans, T. Tsugorka, S. Peng, K. Stauderman, O. Gerasimenko, J. Gerasimenko
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Abstract

Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of CRAC channels has been proposed as a potential treatment and currently, a novel selective CRAC channel inhibitor CM4620 (AuxoraTM, CalciMedica), is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 nM, have been studied against necrosis induced by either bile acids, palmitoleic acid or L-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 nM, and palmitoleic acid starting from 1 nM. Combining CM4620 and galactose (1 mM) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acids-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced oedema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 mM) significantly reduced further necrosis, inflammation, and histopathological score. Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP.
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CRAC通道抑制剂CM4620与半乳糖的联合疗法有望治疗急性胰腺炎
急性胰腺炎(AP)是一种危及生命的炎症性疾病,目前尚无特效疗法。细胞质 Ca2+ 过度升高和细胞内 ATP 耗竭是引发 AP 的原因。目前,一种新型选择性 CRAC 通道抑制剂 CM4620(AuxoraTM,CalciMedica 公司)正在进行 2b 期人体试验。虽然 CM4620 有望成为首个有效治疗 AP 的药物,但它在动物模型中并不能产生完全的保护作用。最近,有一种替代方法建议使用天然碳水化合物半乳糖来减少 ATP 的消耗。在这里,我们研究了将最小有效浓度的 CM4620 与半乳糖结合使用的可能性。我们研究了 CM4620 在 1-100 nM 范围内对胆汁酸、棕榈油酸或 L-天冬酰胺酶诱导的坏死的保护作用。从 50 nM 开始,CM4620 对胆汁酸或天冬酰胺酶诱导的坏死有明显的保护作用;从 1 nM 开始,CM4620 对棕榈油酸诱导的坏死有明显的保护作用。将 CM4620 与半乳糖(1 mM)结合使用,可显著降低坏死程度,使其接近对照组水平。在棕榈油酸-酒精诱导的小鼠 AP 实验模型中,单用 0.1 mg/kg 浓度的 CM4620 可明显减轻水肿、坏死、炎症和组织病理学总评分。0.1 毫克/千克 CM4620 与半乳糖(100 毫摩尔)联合使用可明显减少进一步的坏死、炎症和组织病理学评分。我们的数据表明,CM4620的使用浓度远低于之前的报道,从而减少了潜在的副作用。CM4620 与半乳糖的新型组合可协同作用于 AP 的互补病理机制。
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