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驱动蛋白作为癌症治疗的靶点。

Kinesin motor proteins as targets for cancer therapy.

作者信息

Huszar Dennis, Theoclitou Maria-Elena, Skolnik Jeffrey, Herbst Ronald

机构信息

Cancer Bioscience, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.

出版信息

Cancer Metastasis Rev. 2009 Jun;28(1-2):197-208. doi: 10.1007/s10555-009-9185-8.

Abstract

The process of mitosis is a validated point of intervention in cancer therapy and a variety of anti-mitotic drugs are successfully being used in the clinic. To date, all approved antimitotics target the spindle microtubules, thus interfering with spindle dynamics, leading to mitotic arrest and apoptosis. While effective, these drugs are also associated with a variety of side effects, including neurotoxicity. In recent years, mitotic kinesins have attracted significant attention in the search for novel, alternative mitotic drug targets. Due to their specific function in mitosis, targeting these proteins creates an opportunity for the development of more selective antimitotics with an improved side effect profile. In addition, kinesin inhibitors may overcome resistance to microtubule targeting drugs. Drug discovery efforts in this area have initially focused on the plus-end directed kinesin spindle protein (KSP) and a variety of compounds are currently undergoing clinical testing.

摘要

有丝分裂过程是癌症治疗中一个经过验证的干预靶点,多种抗有丝分裂药物已成功应用于临床。迄今为止,所有获批的抗有丝分裂药物均靶向纺锤体微管,从而干扰纺锤体动力学,导致有丝分裂停滞和细胞凋亡。虽然这些药物有效,但也会引发包括神经毒性在内的多种副作用。近年来,有丝分裂驱动蛋白在寻找新型替代有丝分裂药物靶点方面备受关注。由于它们在有丝分裂中的特定功能,靶向这些蛋白为开发副作用更小、更具选择性的抗有丝分裂药物创造了机会。此外,驱动蛋白抑制剂可能克服对微管靶向药物的耐药性。该领域的药物研发工作最初集中于正向驱动蛋白纺锤体蛋白(KSP),目前有多种化合物正在进行临床试验。

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