AZD7545

AZD7545 is a competitive pyruvate dehydrogenase kinase 2 (PDHK2) inhibitor (IC₅₀=6.4nM) that also inhibits PDHK1 activity (IC₅₀=36.8nM)^[1]. AZD7545 inhibits PDHK activity by disrupting the interaction between PDHK2 and the inner lipoyl domain of the dihydrolipoamide acetyltransferase component of the pyruvate dehydrogenase complex (PDC), thereby increasing the proportion of active PDH^[2]. AZD7545 can be used to study the regulation of glucose metabolism^[3]. AZD7545 also inhibits the growth of drug-resistant melanoma cells^[4].

In vitro, treatment of A549 non-small cell lung cancer cells with AZD7545 (10–20μM) for 4–24 hours effectively inhibited the phosphorylation of pyruvate dehydrogenase (PDH) and enhanced its activity^[5]. Treatment of H1299 non-small cell lung cancer cells with AZD7545 (500μM) alone for 24 hours inhibited PDK1 activity and enhanced PDH activity but did not significantly induce cancer cell apoptosis; however, when combined with the PKM2 activator ML265 (500μmol/L), AZD7545 synergistically inhibited cell proliferation and induced apoptosis, while significantly reducing glucose consumption and lactate production, promoting oxidative phosphorylation metabolic remodeling^[6].

In vivo, administration of AZD7545 (0.5g/L) via drinking water for 5 weeks to 7-week-old ovariectomized (OVX) female C57BL/6J mice significantly suppressed OVX-induced bone loss and reduced the activation of the NFATc1 signaling pathway in osteoclasts^[7]. A single oral dose of AZD7545 (10–30mg/kg) administered to Wistar rats and obese Zucker (fa/fa) rats significantly activated pyruvate dehydrogenase (PDH) in the liver and skeletal muscle and improved blood glucose control in obese Zucker rats^[8].

References:
[1] Morrell JA, Orme J, Butlin RJ, et al. AZD7545 is a selective inhibitor of pyruvate dehydrogenase kinase 2. Biochem Soc Trans. 2003 Dec;31(Pt 6):1168-70.
[2] Kato M, Li J, Chuang JL, et al. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 2007 Aug;15(8):992-1004.
[3] Tuganova A, Klyuyeva A, Popov KM. Recognition of the inner lipoyl-bearing domain of dihydrolipoyl transacetylase and of the blood glucose-lowering compound AZD7545 by pyruvate dehydrogenase kinase 2. Biochemistry. 2007 Jul 24;46(29):8592-602.
[4] Cesi G, Walbrecq G, Zimmer A, et al. ROS production induced by BRAF inhibitor treatment rewires metabolic processes affecting cell growth of melanoma cells. Mol Cancer. 2017 Jun 8;16(1):102.
[5] Jin L, Cho M, Kim BS, et al. Drug evaluation based on phosphomimetic PDHA1 reveals the complexity of activity-related cell death in A549 non-small cell lung cancer cells. BMB Rep. 2021 Nov;54(11):563-568.
[6] Lin H, Han H, Yang M, et al. PKM2/PDK1 dual-targeted shikonin derivatives restore the sensitivity of EGFR-mutated NSCLC cells to gefitinib by remodeling glucose metabolism. Eur J Med Chem. 2023 Mar 5;249:115166.
[7] Lee JM, Kim MJ, Lee SJ, et al. PDK2 Deficiency Prevents Ovariectomy-Induced Bone Loss in Mice by Regulating the RANKL-NFATc1 Pathway During Osteoclastogenesis. J Bone Miner Res. 2021 Mar;36(3):553-566.
[8] Mayers RM, Butlin RJ, Kilgour E, et al. AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats. Biochem Soc Trans. 2003 Dec;31(Pt 6):1165-7.

AZD7545是一种竞争性的丙酮酸脱氢酶激酶2（PDHK2）抑制剂（IC₅₀=6.4nM），同时可抑制PDHK1活力（IC₅₀=36.8nM）^[1]。AZD7545通过破坏PDHK2与丙酮酸脱氢酶复合物（PDC）的二氢硫辛酸乙酰转移酶成分的内部硫辛酰基结构域的相互作用来抑制PDHK活性，从而增加活性PDH的比例^[2]。AZD7545可用于研究葡萄糖代谢的调控机制^[3]。AZD7545还可抑制耐药性黑色素瘤细胞的生长^[4]。

在体外，AZD7545(10–20μM)处理A549非小细胞肺癌细胞4–24小时，能有效抑制丙酮酸脱氢酶（PDH）的磷酸化并增强其活性^[5]。AZD7545（500μM）单独处理H1299非小细胞肺癌细胞24小时，能够抑制PDK1活性并增强PDH活性，但未能显著诱导癌细胞凋亡；而与PKM2激活剂ML265（500μmol/L）联合使用时，可协同抑制细胞增殖并诱导凋亡，同时显著降低葡萄糖消耗和乳酸生成，促进氧化磷酸化代谢重塑^[6]。

在体内，AZD7545（0.5g/L）通过饮用水给药5周，处理7周龄卵巢切除（OVX）雌性C57BL/6J小鼠，AZD7545显著抑制了OVX诱导的骨质流失，同时降低了破骨细胞中NFATc1信号通路的活化^[7]。AZD7545（10-30mg/kg）单次口服给药处理Wistar大鼠和肥胖Zucker（fa/fa）大鼠，显著激活肝脏和骨骼肌中的丙酮酸脱氢酶（PDH），并改善肥胖Zucker大鼠的血糖控制^[8]。