Chromosome Region Maintenance 1 (XPO1/CRM1) as an Anticancer Target and Discovery of Its Inhibitor,Journal of Medicinal Chemistry

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Chromosome Region Maintenance 1 (XPO1/CRM1) as an Anticancer Target and Discovery of Its Inhibitor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-20 , DOI: 10.1021/acs.jmedchem.1c01145
Song Liu ₁ , Wenliang Qiao ₂ , Qingxiang Sun ₃ , Youfu Luo ₁

Affiliation

Chromosome region maintenance 1 (CRM1) is a major nuclear export receptor protein and contributes to cell homeostasis by mediating the transport of cargo from the nucleus to the cytoplasm. CRM1 is a therapeutic target comprised of several tumor types, including osteosarcoma, multiple myeloma, gliomas, and pancreatic cancer. In the past decade, dozens of CRM1 inhibitors have been discovered and developed, including KPT-330, which received FDA approval for multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL) in 2019 and 2020, respectively. This review summarizes the biological functions of CRM1, the current understanding of the role CRM1 plays in cancer, the discovery of CRM1 small-molecule inhibitors, preclinical and clinical studies on KPT-330, and other recently developed inhibitors. A new CRM1 inhibition mechanism and structural dynamics are discussed. Through this review, we hope to guide the future design and optimization of CRM1 inhibitors.

中文翻译：

染色体区域维护 1 (XPO1/CRM1) 作为抗癌靶点及其抑制剂的发现

染色体区域维护 1 (CRM1) 是一种主要的核输出受体蛋白，通过介导货物从细胞核到细胞质的运输来促进细胞稳态。 CRM1 是由多种肿瘤类型组成的治疗靶点，包括骨肉瘤、多发性骨髓瘤、神经胶质瘤和胰腺癌。在过去的十年中，已有数十种CRM1抑制剂被发现和开发，其中包括KPT-330，该药物分别于2019年和2020年获得FDA批准用于治疗多发性骨髓瘤（MM）和弥漫性大B细胞淋巴瘤（DLBCL）。本文综述了CRM1的生物学功能、目前对CRM1在癌症中作用的认识、CRM1小分子抑制剂的发现、KPT-330以及其他最近开发的抑制剂的临床前和临床研究。讨论了新的 CRM1 抑制机制和结构动力学。通过这次综述，我们希望能够指导未来CRM1抑制剂的设计和优化。

更新日期：2021-11-11

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