对PAK2具有10倍选择性的p21活化激酶1 （PAK1）抑制剂的鉴定。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-06-12 DOI:10.1016/j.bmcl.2025.130307

Deidre M. Johns , Jason Olejniczak , Anjali Babbar , Christopher D. Boone , Ozgur Cakici , Melinda Cheng , Qing-Qing Cheng , Alexey Dementiev , Mariam Eick , Nicky Ferdyan , Eric Fontano , Aaron Forman , Ryan Kozlowski , Szu-Wei Lee , Shital Mehta , Kayla Mowery , Brion Murray , Vivian Nguyen , Andrea Olland , Kim B. Phan , Siegfried Reich

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引用次数: 0

摘要

p21活化激酶（PAKs）因其在细胞骨架组织、细胞形态发生和促生存信号传导中的作用而闻名。由于PAK1在肿瘤发生中的作用，在多种癌症中被放大（最普遍的是乳腺癌、卵巢癌和黑色素瘤癌），因此PAK1受到特别关注。PAK2在结构上与PAK1密切相关，但与心脏毒性有关。本文详细介绍了针对PAK1（超过PAK2）选择性小分子抑制剂的基于结构的设计工作。我们在此报道了PAK2的第一个晶体结构，并利用该晶体结构设计了一种PAK1抑制剂，其选择性比PAK2高10倍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Identification of a p21-activated kinase 1 (PAK1) inhibitor with 10-fold selectivity against PAK2

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Identification of a p21-activated kinase 1 (PAK1) inhibitor with 10-fold selectivity against PAK2

The p21-activated kinases (PAKs) are noted for their role in cytoskeletal organization, cellular morphogenesis, and pro-survival signaling. PAK1 is of particular interest due to its role in tumorigenesis, being amplified in multiple cancers (the most prevalent being breast, ovarian, and melanoma cancers). PAK2 is closely related to PAK1 in structure but is associated with cardiotoxicity. A structure-based design effort targeting a PAK1 (over PAK2) selective small molecule inhibitor is detailed herein. We report here the first crystal structure of PAK2 and use this crystal structure to design a PAK1 inhibitor with ten-fold selectivity over PAK2.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.