Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator
| Autor: | Hitoshi Hayasaka, Hiroyuki Hanzawa, Takashi Asahi, Shin-ichi Katakura, Isao Yasumatsu, Kazuo Kanai, Osamu Ubukata, Sachiko Takaishi, Takahiro Kitamura, Yumi Matsui |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Models Molecular Stereochemistry Clinical Biochemistry Pyruvate Kinase Pharmaceutical Science Antineoplastic Agents PKM2 Ligands Biochemistry 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Cell Line Tumor Drug Discovery Humans Glycolysis Binding site Molecular Biology Cell Proliferation Ligand efficiency Dose-Response Relationship Drug Molecular Structure Cell growth Chemistry Activator (genetics) Organic Chemistry High-Throughput Screening Assays 030104 developmental biology Anaerobic glycolysis 030220 oncology & carcinogenesis Molecular Medicine Thermodynamics Drug Screening Assays Antitumor Pyruvate kinase |
| Zdroj: | Bioorganicmedicinal chemistry. 25(13) |
| ISSN: | 1464-3391 |
| Popis: | Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target. To obtain novel PKM2 activators, we conducted a high-throughput screening (HTS). Among several hit compounds, a fragment-like hit compound with low potency but high ligand efficiency was identified. Two molecules of the hit compound bound at one activator binding site, and the molecules were linked based on the crystal structure. Since this linkage succeeded in maintaining the original position of the hit compound, the obtained compound exhibited highly improved potency in an in vitro assay. The linked compound also showed PKM2 activating activity in a cell based assay, and cellular growth inhibition of the A549 cancer cell line. Discovery of this novel scaffold and binding mode of the linked compound provides a valuable platform for the structure-guided design of PKM2 activators. |
| Databáze: | OpenAIRE |
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