Development of Low-Molecular-Weight Compounds Targeting the Cancer-Associated KLF5 Transcription Factor,ACS Medicinal Chemistry Letters

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Development of Low-Molecular-Weight Compounds Targeting the Cancer-Associated KLF5 Transcription Factor
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2022-03-28 , DOI: 10.1021/acsmedchemlett.1c00721
Takeo Nakaya ₁ , Kenichi Aizawa ₂ , Yuki Taguchi _{3,

4} , Kentaro Tsuji ₁ , Sachi Sekine ₅ , Kazuhiro Murakami _{1,

6} , Masaji Kasai ₇ , Hirofumi Nakano ₇ , Yasumitsu Kondoh ₈ , Shingo Dan ₉ , Atsushi Yoshimori ₁₀ , Hiroyuki Kouji _{7,

11} , Dai Takehara ₇ , Toru Suzuki ₁₂ , Hiroyuki Osada ₈ , Masayuki Murata _{3,

4} , Akira Tanaka ₁ , Ryozo Nagai ₁₃

Affiliation

Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
Department of Clinical Pharmacology, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Meguro-ku, Tokyo 153-8902, Japan.
Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8503, Japan.
Department of Pathology and Department of Pediatric Surgery , Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
Department of Dentistry and Oral Surgery, Jichi Medical University, Shimotsuke, Tochigi 329-0498, Japan.
PRISM BioLab Co., Ltd., Fujisawa, Kanagawa 251-8555, Japan.
Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
Institute for Theoretical Medicine, Inc., Fujisawa Kanagawa 251-0012, Japan.
¶Oita University Institute of Advanced Medicine, Inc., Fujisawa, Kanagawa 251-0052, Japan.
Department of Cardiovascular Sciences, University of Leicester Cardiovascular Research Centre, Glenfield Hospital, Leicester LE39QP, U.K.
Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan.

Krüppel-like factor 5 (KLF5) is a potential target for anticancer drugs. However, as an intrinsically disordered protein (IDP) whose tertiary structure cannot be solved, innovative strategies are needed. We focused on its hydrophobic α-helix structure, defined as an induced helical motif (IHM), which is a possible interface for protein–protein interaction. Using mathematical analyses predicting the α-helix’s structure and hydrophobicity, a 4-amino-acid site (V-A-I-F) was identified as an IHM. Low-molecular-weight compounds that mimic the main chain conformation of the α-helix with the four side chains of V-A-I-F were synthesized using bicyclic pyrazinooxadiazine-4,7-dione. These compounds selectively suppressed the proliferation and survival of cancer cells but not noncancer cells and decreased the protein but not mRNA levels of KLF5 in addition to reducing proteins of Wnt signaling. The compounds further suppressed transplanted colorectal cancer cells in vivo without side effects. Our approach appears promising for developing drugs against key IDPs.

中文翻译：

开发靶向癌症相关 KLF5 转录因子的低分子量化合物

Krüppel 样因子 5 (KLF5) 是抗癌药物的潜在靶标。然而，作为一种本质上无序的蛋白质 (IDP)，其三级结构无法解析，因此需要创新策略。我们专注于其疏水性 α-螺旋结构，定义为诱导螺旋基序 (IHM)，这是蛋白质-蛋白质相互作用的可能界面。使用预测 α-螺旋结构和疏水性的数学分析，4-氨基酸位点 (VAIF) 被确定为 IHM。使用双环吡嗪并恶二嗪-4,7-二酮合成了模拟具有 VAIF 四个侧链的 α-螺旋主链构象的低分子量化合物。这些化合物选择性地抑制癌细胞而非非癌细胞的增殖和存活，除了减少 Wnt 信号传导的蛋白质外，还降低了 KLF5 的蛋白质水平而不是 mRNA 水平。这些化合物进一步抑制了移植的结直肠癌细胞体内无副作用。我们的方法似乎有希望开发针对主要国内流离失所者的药物。

更新日期：2022-03-28

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