Suppr超能文献

基于高通量筛选和结构的吲唑衍生的ULK1抑制剂优化

HTS and Structure Based Optimization of Indazole-Derived ULK1 Inhibitors.

作者信息

Wood Spencer D, Grant Wayne, Adrados Isabel, Choi Jun Yong, Alburger James M, Duckett Derek R, Roush William R

机构信息

Department of Chemistry and Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, United States.

出版信息

ACS Med Chem Lett. 2017 Nov 22;8(12):1258-1263. doi: 10.1021/acsmedchemlett.7b00344. eCollection 2017 Dec 14.

Abstract

We present the outcome of an high throughput screen (HTS) and optimization of a small molecule Unc-51-Like Kinase 1 (ULK1) inhibitor hit, , with an indazole core. Docking studies guided design efforts that led to inhibitors with increased activity vs ULK1 (IC < 50 nM). The most advanced molecules in this inhibitor series ( and ) hold promise for further development into selective ULK1 molecular probes to interrogate the biology of ULK1 and to assess whether selectively targeting autophagy is an effective anticancer strategy.

摘要

我们展示了一种高通量筛选(HTS)的结果以及对一种具有吲唑核心的小分子Unc-51样激酶1(ULK1)抑制剂命中物的优化。对接研究指导了设计工作,从而得到了对ULK1活性增强的抑制剂(IC<50 nM)。该抑制剂系列中最先进的分子(和)有望进一步开发成选择性ULK1分子探针,以探究ULK1的生物学特性,并评估选择性靶向自噬是否是一种有效的抗癌策略。

相似文献

1
HTS and Structure Based Optimization of Indazole-Derived ULK1 Inhibitors.
ACS Med Chem Lett. 2017 Nov 22;8(12):1258-1263. doi: 10.1021/acsmedchemlett.7b00344. eCollection 2017 Dec 14.
2
Development of an HTS-Compatible Assay for the Discovery of Ulk1 Inhibitors.
J Biomol Screen. 2015 Aug;20(7):913-20. doi: 10.1177/1087057115579391. Epub 2015 Apr 7.
3
Development of potent and selective ULK1/2 inhibitors based on 7-azaindole scaffold with favorable in vivo properties.
Eur J Med Chem. 2024 Feb 15;266:116101. doi: 10.1016/j.ejmech.2023.116101. Epub 2023 Dec 29.
4
Discovery of a small molecule targeting ULK1-modulated cell death of triple negative breast cancer and .
Chem Sci. 2017 Apr 1;8(4):2687-2701. doi: 10.1039/c6sc05368h. Epub 2017 Jan 9.
5
Unc-51 like kinase 1 (ULK1) in silico analysis for biomarker identification: a vital component of autophagy.
Gene. 2015 May 10;562(1):40-9. doi: 10.1016/j.gene.2015.02.056. Epub 2015 Feb 19.
6
Discovery of novel inhibitors of Aurora kinases with indazole scaffold: In silico fragment-based and knowledge-based drug design.
Eur J Med Chem. 2016 Nov 29;124:186-199. doi: 10.1016/j.ejmech.2016.08.026. Epub 2016 Aug 16.
7
Small-Molecule Activator of UNC-51-Like Kinase 1 (ULK1) That Induces Cytoprotective Autophagy for Parkinson's Disease Treatment.
J Med Chem. 2018 Apr 12;61(7):2776-2792. doi: 10.1021/acs.jmedchem.7b01575. Epub 2018 Mar 29.
8
Study of ULK1 Catalytic Activity and Its Regulation.
Methods Enzymol. 2017;587:391-404. doi: 10.1016/bs.mie.2016.09.067. Epub 2016 Nov 18.
9
Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates.
Mol Cell. 2015 Jul 16;59(2):285-97. doi: 10.1016/j.molcel.2015.05.031. Epub 2015 Jun 25.

引用本文的文献

1
Discovery of novel ULK1 inhibitors through machine learning-guided virtual screening and biological evaluation.
Future Med Chem. 2024;16(18):1821-1837. doi: 10.1080/17568919.2024.2385288. Epub 2024 Aug 15.
2
Blockage of Autophagy for Cancer Therapy: A Comprehensive Review.
Int J Mol Sci. 2024 Jul 7;25(13):7459. doi: 10.3390/ijms25137459.
3
Autophagy and Glycometabolic Reprograming in the Malignant Progression of Lung Cancer: A Review.
Technol Cancer Res Treat. 2023 Jan-Dec;22:15330338231190545. doi: 10.1177/15330338231190545.
5
Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications.
Acta Pharm Sin B. 2022 Oct;12(10):3743-3782. doi: 10.1016/j.apsb.2022.06.004. Epub 2022 Jun 11.
6
Targeted Protein Degradation via Lysosomes.
Biochemistry. 2023 Feb 7;62(3):564-579. doi: 10.1021/acs.biochem.2c00310. Epub 2022 Sep 21.
7
Inhibiting Cytoprotective Autophagy in Cancer Therapy: An Update on Pharmacological Small-Molecule Compounds.
Front Pharmacol. 2022 Aug 11;13:966012. doi: 10.3389/fphar.2022.966012. eCollection 2022.
8
Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer.
RSC Adv. 2021 Jul 20;11(41):25228-25257. doi: 10.1039/d1ra03979b. eCollection 2021 Jul 19.
9
Therapeutic Targeting of Autophagy in Pancreatic Ductal Adenocarcinoma.
Front Pharmacol. 2021 Nov 30;12:751568. doi: 10.3389/fphar.2021.751568. eCollection 2021.
10
Stapled Peptide Inhibitors of Autophagy Adapter LC3B.
Chembiochem. 2020 Oct 1;21(19):2777-2785. doi: 10.1002/cbic.202000212. Epub 2020 Jun 22.

本文引用的文献

1
Software for molecular docking: a review.
Biophys Rev. 2017 Apr;9(2):91-102. doi: 10.1007/s12551-016-0247-1. Epub 2017 Jan 16.
2
Discovery and structure of a new inhibitor scaffold of the autophagy initiating kinase ULK1.
Bioorg Med Chem. 2015 Sep 1;23(17):5483-8. doi: 10.1016/j.bmc.2015.07.034. Epub 2015 Jul 26.
3
Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates.
Mol Cell. 2015 Jul 16;59(2):285-97. doi: 10.1016/j.molcel.2015.05.031. Epub 2015 Jun 25.
4
Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.
Cell. 2015 Jun 4;161(6):1252-65. doi: 10.1016/j.cell.2015.05.023.
5
Development of an HTS-Compatible Assay for the Discovery of Ulk1 Inhibitors.
J Biomol Screen. 2015 Aug;20(7):913-20. doi: 10.1177/1087057115579391. Epub 2015 Apr 7.
6
Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy.
J Biol Chem. 2015 May 1;290(18):11376-83. doi: 10.1074/jbc.C114.627778. Epub 2015 Apr 1.
7
The role for autophagy in cancer.
J Clin Invest. 2015 Jan;125(1):42-6. doi: 10.1172/JCI73941. Epub 2015 Jan 2.
8
Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors.
ACS Chem Biol. 2015 Jan 16;10(1):257-61. doi: 10.1021/cb500835z. Epub 2015 Jan 6.
9
Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.
Cancer Discov. 2014 Aug;4(8):905-13. doi: 10.1158/2159-8290.CD-14-0362. Epub 2014 May 29.
10
Autophagy and cancer therapy.
Mol Pharmacol. 2014 Jun;85(6):830-8. doi: 10.1124/mol.114.091850. Epub 2014 Feb 26.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验