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一种新型的威特综合征相关蛋白激活剂，具有血液系统恶性肿瘤的抗肿瘤活性。

A first-in-class Wiskott-Aldrich syndrome protein activator with antitumor activity in hematologic cancers.

机构信息

Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona.

Institute of Research in Biomedicine, Faculty of Biomedical Sciences, USI, Bellinzona.

出版信息

Haematologica. 2024 Nov 1;109(11):3602-3614. doi: 10.3324/haematol.2022.282672.

DOI:10.3324/haematol.2022.282672
PMID:
38899342
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11532693/
Abstract

Hematologic cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the autoinhibited form of WASp. EG-011 possesses in vitro and in vivo antitumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding were demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs inducing actin polymerization.

摘要

血液系统癌症是成人和儿童中最常见的癌症之一。尽管治疗方法有了显著的改进，但仍有许多患者死于该疾病。因此，需要新的治疗方法。Wiskott-Aldrich 综合征蛋白 (WASp) 家族与 Arp2/3 复合物一起调节肌动蛋白组装，该复合物是一种普遍存在的成核因子。WASp 仅在造血细胞中表达，并存在两种变构构象：自身抑制或激活。在这里，我们描述了 EG-011 的开发，这是一种新型的 WASp 自身抑制形式的小分子激活剂。EG-011 作为单一药物在淋巴瘤、白血病和多发性骨髓瘤中具有体外和体内抗肿瘤活性，包括对 PI3K、BTK 和蛋白酶体抑制剂的继发性耐药模型。在淋巴瘤异种移植模型中证实了体外活性。使用多种技术证明了肌动蛋白聚合和 WASp 结合。转录组分析突出了与诱导肌动蛋白聚合的药物的同源性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/c5d37138d635/1093602.fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/7667f9da6fe0/1093602.fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/aa7b671b9ee6/1093602.fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/02bf994e5280/1093602.fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/9d0774f5b02b/1093602.fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/c5d37138d635/1093602.fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/7667f9da6fe0/1093602.fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/aa7b671b9ee6/1093602.fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/02bf994e5280/1093602.fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/9d0774f5b02b/1093602.fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3cbc/11532693/c5d37138d635/1093602.fig5.jpg

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