Highly expressed in cancer 1 (Hec1) plays an essential role in mitosis and is correlated with cancer formation, progression, and survival. Phosphorylation of Hec1 by Nek2 kinase is essential for its mitotic function, thus any disruption of Hec1/Nek2 protein-protein interaction has potential for cancer therapy. We have developed T-1101 tosylate (9j tosylate, 9j formerly known as TAI-95), optimized from 4-aryl-N-pyridinylcarbonyl-2-aminothiazole of scaffold 9 by introducing various C-4' substituents to enhance potency and water solubility, as a first-in-class oral clinical candidate for Hec1 inhibition with potential for cancer therapy. T-1101 has good oral absorption, along with potent in vitro antiproliferative activity (IC50: 14.8-21.5 nM). It can achieve high concentrations in Huh-7 and MDA-MB-231 tumor tissues, and showed promise in antitumor activity in mice bearing human tumor xenografts of liver cancer (Huh-7), as well as of breast cancer (BT474, MDA-MB-231, and MCF7) with oral administration. Oral co-administration of T-1101 halved the dose of sorafenib (25 mg/kg to 12.5 mg/kg) required to exhibit comparable in vivo activity towards Huh-7 xenografts. Cellular events resulting from Hec1/Nek2 inhibition with T-1101 treatment include Nek2 degradation, chromosomal misalignment, and apoptotic cell death. A combination of T-1101 with either of doxorubicin, paclitaxel, and topotecan in select cancer cells also resulted in synergistic effects. Inactivity of T-1101 on non-cancerous cells, a panel of kinases, and hERG demonstrates cancer specificity, target specificity, and cardiac safety, respectively. Subsequent salt screening showed that T-1101 tosylate has good oral AUC (62.5 μM·h), bioavailability (F = 77.4%), and thermal stability. T-1101 tosylate is currently in phase I clinical trials as an orally administered drug for cancer therapy.

中文翻译：

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发现T-1101甲苯磺酸盐是癌症治疗中Hec1 / Nek2抑制的一流临床候选药物。

在癌症1（Hec1）中高表达在有丝分裂中起着至关重要的作用，并且与癌症的形成，进展和生存相关。Nek2激酶使Hec1磷酸化对于其有丝分裂功能至关重要，因此，任何破坏Hec1 / Nek2蛋白质-蛋白质相互作用的方法都具有潜在的癌症治疗潜力。我们开发了T-1101甲苯磺酸酯（9j甲苯磺酸酯，以前称为TAI-95的9j），是通过引入各种C-4'取代基以增强效能和水溶性从支架9的4-芳基-N-吡啶基羰基-2-氨基噻唑进行优化的，作为具有治疗癌症潜力的Hec1抑制的一流口服临床候选药物。T-1101具有良好的口服吸收以及强大的体外抗增殖活性（IC50：14.8-21.5 nM）。它可以在Huh-7和MDA-MB-231肿瘤组织中达到高浓度，并在口服人类肝癌（Huh-7）和乳腺癌（BT474，MDA-MB-231和MCF7）的人类肿瘤异种移植物的小鼠中显示出抗肿瘤活性。T-1101的口服共同给药使索拉非尼对Huh-7异种移植物具有可比的体内活性所需的剂量减半（25 mg / kg至12.5 mg / kg）。用T-1101处理抑制Hec1 / Nek2引起的细胞事件包括Nek2降解，染色体错位和凋亡性细胞死亡。在选定的癌细胞中，T-1101与阿霉素，紫杉醇和托泊替康中的任何一种的组合也产生协同作用。T-1101对非癌细胞，一组激酶和hERG的无活性分别证明了癌症特异性，靶标特异性和心脏安全性。随后的盐筛查表明，甲苯磺酸T-1101具有良好的口服AUC（62.5μM·h），生物利用度（F = 77.4％）和热稳定性。T-1101甲苯磺酸酯目前正处于I期临床试验中，作为一种口服药物用于癌症治疗。