Hesperadin

Hesperadin is an ATP competitive indolinone inhibitor of Aurora B with an IC₅₀ of 250nM^[1]. Aurora B kinase is a key serine/threonine kinase that regulates chromosome segregation and cytokinesis during cell mitosis^[2]. Hesperadin inhibits kinase activity through the ATP competition mechanism and is usually used in the research of cancer, malaria and influenza virus infections by inhibiting^[3].

In vitro, treatment of HeLa cells with Hesperadin (50 or 100nM; 20h) inhibits Aurora B kinase activity, abolishes histone H3 Ser10 phosphorylation, prevents chromosome alignment, permits anaphase entry with monooriented chromosomes, stalls cytokinesis, generates polyploid nuclei, overrides taxol- and monastrol-induced mitotic arrest within 1h, and reduces BubR1 kinetochore recruitment^[4]. Treatment of Miapaca-2 and BxPC-3 cells with Hesperadin (50-100nM; 48–72h) inhibits cell proliferation, abolishes DNA synthesis, blocks colony formation, arrests cells in G2/M, induces polyploidy, collapses mitochondrial membrane potential and ATP content, elevates intracellular ROS, and drives caspase-3/PARP cleavage and apoptosis in Miapaca-2 and BxPC-3 cells^[5].

In vivo, Hesperadin (2.5μg/kg/day; i.p.; 4 weeks) reduced cardiac infarct size, decreased serum LDH concentration, and attenuated cardiac cell death and DNA damage in a mouse model of acute ischemia/reperfusion injury^[6]. Hesperadin (0.5μg/μl; 12h; intracerebroventricular injection) decreased brain edema, improved neurobehavioral function, reduced MST4 expression, increased pAKT levels, and attenuated autophagy in the perihematoma brain tissue of intracerebral hemorrhage mice^[7].

References:
[1] Jetton N, Rothberg KG, Hubbard JG, et al. The cell cycle as a therapeutic target against Trypanosoma brucei: Hesperadin inhibits Aurora kinase-1 and blocks mitotic progression in bloodstream forms. Mol Microbiol. 2009;72(2):442-458.
[2] Krenn V, Musacchio A. The Aurora B Kinase in Chromosome Bi-Orientation and Spindle Checkpoint Signaling. Front Oncol. 2015;5:225.
[3] Hu Y, Zhang J, Musharrafieh R, Hau R, Ma C, Wang J. Chemical Genomics Approach Leads to the Identification of Hesperadin, an Aurora B Kinase Inhibitor, as a Broad-Spectrum Influenza Antiviral. Int J Mol Sci. 2017;18(9):1929.
[4] Hauf S, Cole RW, LaTerra S, et al. The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint. J Cell Biol. 2003;161(2):281-294.
[5] Zhang Y, Wu J, Fu Y, et al. Hesperadin suppresses pancreatic cancer through ATF4/GADD45A axis at nanomolar concentrations. Oncogene. 2022;41(25):3394-3408.
[6] Zhang J, Liang R, Wang K, et al. Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth. Circulation. 2022;145(15):1154-1168.
[7] Wu X, Wu J, Hu W, et al. MST4 Kinase Inhibitor Hesperadin Attenuates Autophagy and Behavioral Disorder via the MST4/AKT Pathway in Intracerebral Hemorrhage Mice. Behav Neurol. 2020;2020:2476861.

Hesperadin是一种竞争性ATP结合抑制剂，对Aurora B激酶的IC₅₀为250nM^[1]。Aurora B激酶是一种关键的丝氨酸/苏氨酸激酶，调控细胞有丝分裂中的染色体分离和细胞质分裂^[2]。Hesperadin通过ATP竞争抑制激酶活性，常用于癌症、疟疾和流感病毒感染研究^[3]。

体外实验中，Hesperadin（50或100nM；20小时）处理HeLa细胞抑制Aurora B激酶活性，消除组蛋白H3 Ser10磷酸化，阻止染色体排列，允许单极染色体进入有丝分裂后期，阻滞细胞质分裂，导致多倍体核形成，在1小时内解除Taxol和Monastrol诱导的有丝分裂阻滞，并减少BubR1着丝粒招募^[4]。Hesperadin（50 - 100nM；48 - 72小时）处理Miapaca-2和BxPC-3细胞抑制细胞增殖，消除DNA合成，阻断集落形成，使细胞在G2/M期停滞，诱导多倍体形成，破坏线粒体膜电位和ATP含量，增加细胞内ROS，并在Miapaca - 2和BxPC - 3细胞中驱动caspase-3/PARP切割和凋亡^[5]。

体内实验中，Hesperadin（2.5μg/kg/天；腹腔注射；4周）在急性缺血/再灌注损伤小鼠模型中减少心肌梗死面积，降低血清LDH浓度，减轻心肌细胞死亡和DNA损伤^[6]。Hesperadin（0.5μg/μl；12小时；脑内注射）减少脑出血小鼠脑出血周边脑组织的脑水肿，改善神经行为功能，降低MST4表达，提高pAKT水平，并减少自噬^[7]。