Discovery of macrocyclic CDK2/4/6 inhibitors with improved potency and DMPK properties through a highly efficient macrocyclic drug design platform
Copyright © 2024 Elsevier Inc. All rights reserved..
Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified compound 8 as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:146 |
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| Enthalten in: |
Bioorganic chemistry - 146(2024) vom: 26. Apr., Seite 107285 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Meng, Fanye [VerfasserIn] |
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| Links: |
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| Themen: |
CDK2/4/6 |
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| Anmerkungen: |
Date Completed 15.04.2024 Date Revised 15.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2024.107285 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM370372565 |
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| 520 | |a Cyclin-dependent kinases (CDKs) are critical cell cycle regulators that are often overexpressed in tumors, making them promising targets for anti-cancer therapies. Despite substantial advancements in optimizing the selectivity and drug-like properties of CDK inhibitors, safety of multi-target inhibitors remains a significant challenge. Macrocyclization is a promising drug discovery strategy to improve the pharmacological properties of existing compounds. Here we report the development of a macrocyclization platform that enabled the highly efficient discovery of a novel, macrocyclic CDK2/4/6 inhibitor from an acyclic precursor (NUV422). Using dihedral angle scan and structure-based, computer-aided drug design to select an optimal ring-closing site and linker length for the macrocycle, we identified compound 8 as a potent new CDK2/4/6 inhibitor with optimized cellular potency and safety profile compared to NUV422. Our platform leverages both experimentally-solved as well as generative chemistry-derived macrocyclic structures and can be deployed to streamline the design of macrocyclic new drugs from acyclic starting compounds, yielding macrocyclic compounds with enhanced potency and improved drug-like properties | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Cyclin-dependent kinases | |
| 650 | 4 | |a Enhanced drug-like properties | |
| 650 | 4 | |a Macrocyclization platform | |
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| 700 | 1 | |a Liu, Jinxin |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Zhongying |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Jiaojiao |e verfasserin |4 aut | |
| 700 | 1 | |a Steurer, Barbara |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yilin |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yazhou |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Man |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Aliper, Alex |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Xiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhavoronkov, Alex |e verfasserin |4 aut | |
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