Hedgehog-Gli signaling pathway inhibitors as anticancer agents.
Hedgehog-Gli signaling pathway inhibitors as anticancer agents.
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DOI：
10.1021/jm801420y
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发表时间：
2009-07-09
影响因子：
7.3
通讯作者：
Fujii N
中科院分区：
文献类型：
--
作者：
Mahindroo N;Punchihewa C;Fujii N
在过去的几年里，癌症药物的发现经历了范式的转变，从主要基于细胞毒性药物的治疗转向针对遗传和分子靶点的治疗，这要归功于对癌症发生和发展的基因和途径以及新药物发现技术的不断了解。曲妥珠单抗、伊马替尼、吉非替尼和厄洛替尼等药物的成功证明，靶向特定的致癌信号转导途径在临床上是有用的。 1 Hedgehog-神经胶质瘤相关癌基因同源物锌指蛋白 (Hh-Glia) 信号通路就是此类通路之一，在过去十年中吸引了药物发现科学家。 Hh-Gli 信号传导在许多组织和体细胞结构的胚胎模式和发育以及成人成熟组织的维持和修复中发挥着重要作用。 2-4 Hh-Gli 通路不受控制的激活与多种癌症有关，包括髓母细胞瘤、横纹肌肉瘤、黑色素瘤、基底细胞癌以及乳腺癌、肺癌、肝癌、胃癌、前列腺癌和胰腺癌。 2, 5-8 异常 Hh-Gli 通路的抑制（图 1）因此成为抗癌治疗的一个有吸引力的目标。 9-11 一种 Hh 通路抑制剂在 I 期临床试验中显示出有希望的结果，并正在进行 II12 期研究，另外两种化合物已进入 I 期临床试验。 13, 14 在本文中，我们回顾了医学* 应向谁发送信件。电话：(+ 1) 901 595 5871。传真：(+ 1) 901 595 5715。电子邮件：Neeraj。 Mahindroo@stjude。组织。 a 缩写：Hh，刺猬； Gli，神经胶质瘤相关癌基因同源物锌指蛋白；嘘，索尼克刺猬；嗯，沙漠刺猬；呃，印度刺猬； Smo，平滑；打补丁，打补丁；福，融合； SuFu，融合抑制器； Cos2、Costal-2； PKA，蛋白激酶A； GSK3，糖原合酶激酶3； CK1，酪蛋白激酶1； BCC，基底细胞癌； GS，戈林综合征； Adh7，乙醇脱氢酶7； Raldh2，视网膜脱氢酶2； MTP，微粒体甘油三酯转移蛋白； PTHrP，甲状旁腺激素相关肽； BMP 2，骨形态发生蛋白-2； Dyrk，双特异性酪氨酸磷酸化调节激酶； IFT，鞭毛内转运蛋白； Ras，大鼠肉瘤； Akt，蛋白激酶 B； MEK，丝裂原激活蛋白/细胞外信号调节激酶； ERK，细胞外调节激酶； PKC，蛋白激酶C。
Cancer drug discovery has undergone a paradigm change over the past few years, from predominantly cytotoxic agent-based therapy to therapy aimed at genetic and molecular targets, thanks to a growing understanding of the genes and pathways responsible for cancer initiation and progression and to new drug discovery technologies. The success of drugs like trastuzumab, imatinib, gefitinib, and erlotinib has demonstrated that the targeting of specific oncogenic signal transduction pathways can be clinically useful. 1 One such pathway, the Hedgehog-gliomaassociated oncogene homologue zinc finger protein (Hh-Glia) signaling pathway, has attracted drug discovery scientists for the past decade. Hh-Gli signaling plays an important role in the embryonic patterning and development of many tissues and somatic structures as well as maintaining and repairing mature tissues in adults. 2-4 Uncontrolled activation of the Hh-Gli pathway has been implicated in several cancers, including medulloblastoma, rhabdomyosarcoma, melanoma, basal cell carcinoma, and breast, lung, liver, stomach, prostate, and pancreatic cancers. 2, 5-8 Inhibition of the aberrant Hh-Gli pathway (Figure 1) has thus emerged as an attractive target for anticancer therapy. 9-11 One Hh pathway inhibitor has shown promising results in phase I clinical trials and is proceeding to phase II12 studies, and two other compounds have entered phase I clinical trials. 13, 14 In this article, we review the medicinal* To whom correspondence should be addressed. Phone:(+ 1) 901 595 5871. Fax:(+ 1) 901 595 5715. E-mail: Neeraj. Mahindroo@ stjude. org. a Abbreviations: Hh, Hedgehog; Gli, glioma-associated oncogene homologue zinc finger protein; Shh, Sonic hedgehog; Dhh, Desert hedgehog; Ihh, Indian hedgehog; Smo, Smoothened; Ptch, Patched; Fu, Fused; SuFu, Suppressor of Fused; Cos2, Costal-2; PKA, protein kinase A; GSK3, glycogen synthase kinase 3; CK1, casein kinase 1; BCC, basal cell carcinoma; GS, Gorlin syndrome; Adh7, alcohol dehydrogenase 7; Raldh2, retinal dehydrogenase 2; MTP, microsomal triglyceride transfer protein; PTHrP, parathyroid hormone-related peptide; BMP 2, bone-morphogenetic protein-2; Dyrk, dual specificity tyrosine phosphorylation regulated kinase; IFT, intraflagellar transport protein; Ras, rat sarcoma; Akt, protein kinase B; MEK, mitogen-activated protein/extracellular signal-regulated kinase; ERK, extracellular regulated kinases; PKC, protein kinase C.
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