School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom (T.L., C.A.L., T.D.B.); and Centre for Drug Discovery and Development, Sansom Institute for Health Research, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.W.).
School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, United Kingdom (T.L., C.A.L., T.D.B.); and Centre for Drug Discovery and Development, Sansom Institute for Health Research, and School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia (S.W.)
Mol Pharmacol. 2015 Jan;87(1):18-30. doi: 10.1124/mol.114.093245. Epub 2014 Oct 14.
ON01910.Na [sodium (E)-2-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)phenylamino)acetate; Rigosertib, Estybon], a styryl benzylsulfone, is a phase III stage anticancer agent. This non-ATP competitive kinase inhibitor has multitargeted activity, promoting mitotic arrest and apoptosis. Extensive phase I/II studies with ON01910.Na, conducted in patients with solid tumors and hematologic cancers, demonstrate excellent efficacy. However, issues remain affecting its development. These include incomplete understanding of antitumor mechanisms, low oral bioavailability, and unpredictable pharmacokinetics. We have identified a novel (E)-styrylsulfonyl methylpyridine [(E)-N-(2-methoxy-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)pyridin-3-yl)methanesulfonamide (TL-77)] which has shown improved oral bioavailability compared with ON01910.Na. Here, we present detailed cellular mechanisms of TL-77 in comparison with ON01910.Na. TL-77 displays potent growth inhibitory activity in vitro (GI50 < 1μM against HCT-116 cells), demonstrating 3- to 10-fold greater potency against tumor cell lines when compared with normal cells. Cell-cycle analyses reveal that TL-77 causes significant G2/M arrest in cancer cells, followed by the onset of apoptosis. In cell-free conditions, TL-77 potently inhibits tubulin polymerization. Mitotically arrested cells display multipolar spindles and misalignment of chromosomes, indicating that TL-77 interferes with mitotic spindle assembly in cancer cells. These effects are accompanied by induction of DNA damage, inhibition of Cdc25C phosphorylation [indicative of Plk1 inhibition], and downstream inhibition of cyclin B1. However, kinase assays failed to confirm inhibition of Plk1. Nonsignificant effects on phosphoinositide 3-kinase/Akt signal transduction were observed after TL-77 treatment. Analysis of apoptotic signaling pathways reveals that TL-77 downregulates expression of B-cell lymphoma 2 family proteins (Bid, Bcl-xl, and Mcl-1) and stimulates caspase activation. Taken together, TL-77 represents a promising anticancer agent worthy of further evaluation.
ON01910.Na [钠（E）-2-（2-甲氧基-5-（（2,4,6-三甲氧基苯乙烯基磺酰基）甲基）氨基）乙酸盐；Rigosertib，Estybon]，一种苯乙烯基苄基砜，是一种处于 III 期临床试验阶段的抗癌药物。这种非 ATP 竞争性激酶抑制剂具有多靶点活性，可促进有丝分裂停滞和细胞凋亡。在实体瘤和血液系统恶性肿瘤患者中进行的广泛的 I/II 期研究表明，ON01910.Na 具有优异的疗效。然而，其发展仍存在一些问题。其中包括对抗肿瘤机制的不完全了解、口服生物利用度低和不可预测的药代动力学。我们已经确定了一种新型（E）-苯乙烯基磺酰基甲基吡啶[（E）-N-（2-甲氧基-5-（（2,4,6-三甲氧基苯乙烯基磺酰基）甲基）吡啶-3-基）甲磺酰胺（TL-77）]，与 ON01910.Na 相比，它具有更高的口服生物利用度。在这里，我们比较了 TL-77 与 ON01910.Na 的详细细胞机制。TL-77 在体外具有很强的生长抑制活性（对 HCT-116 细胞的 GI50<1μM），与正常细胞相比，对肿瘤细胞系的活性高出 3 至 10 倍。细胞周期分析显示，TL-77 可导致癌细胞中显著的 G2/M 期阻滞，随后发生细胞凋亡。在无细胞条件下，TL-77 可强烈抑制微管聚合。有丝分裂期被阻滞的细胞显示出多极纺锤体和染色体排列不齐，表明 TL-77 干扰了癌细胞有丝分裂纺锤体的组装。这些作用伴随着 DNA 损伤的诱导、Cdc25C 磷酸化的抑制[表明 Plk1 的抑制]以及细胞周期蛋白 B1 的下游抑制。然而，激酶测定未能证实 Plk1 的抑制。TL-77 处理后，磷酸肌醇 3-激酶/Akt 信号转导未见明显影响。凋亡信号通路分析显示，TL-77 下调 B 细胞淋巴瘤 2 家族蛋白（Bid、Bcl-xl 和 Mcl-1）的表达并刺激半胱天冬酶的激活。总之，TL-77 是一种很有前途的抗癌药物，值得进一步评估。
