Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors
Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly e...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-01-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/22/2/635 |
id |
doaj-b80db90e1246432084f58339bd079ac1 |
---|---|
record_format |
Article |
spelling |
doaj-b80db90e1246432084f58339bd079ac12021-01-11T00:02:11ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-01-012263563510.3390/ijms22020635Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 InhibitorsMathias Elsocht0Philippe Giron1Laila Maes2Wim Versées3Gustavo J. Gutierrez4Jacques De Grève5Steven Ballet6Research Group of Organic Chemistry, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, BelgiumLaboratory of Medical and Molecular Oncology and Center of Medical Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, BelgiumVIB-VUB Center for Structural Biology, Pleinlaan 2, 1050 Brussels, BelgiumVIB-VUB Center for Structural Biology, Pleinlaan 2, 1050 Brussels, BelgiumLaboratory of Pathophysiological Cell Signalling (PACS), Department of Biology, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, BelgiumLaboratory of Medical and Molecular Oncology and Center of Medical Genetics, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090 Brussels, BelgiumResearch Group of Organic Chemistry, Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, BelgiumLung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4’ of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present <i>N</i>-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC<sub>50</sub>~1 µM) with moderate selectivity over other kinases.https://www.mdpi.com/1422-0067/22/2/635non-small cell lung cancerUSP13NEK4EGFRquinazolinamines |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mathias Elsocht Philippe Giron Laila Maes Wim Versées Gustavo J. Gutierrez Jacques De Grève Steven Ballet |
spellingShingle |
Mathias Elsocht Philippe Giron Laila Maes Wim Versées Gustavo J. Gutierrez Jacques De Grève Steven Ballet Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors International Journal of Molecular Sciences non-small cell lung cancer USP13 NEK4 EGFR quinazolinamines |
author_facet |
Mathias Elsocht Philippe Giron Laila Maes Wim Versées Gustavo J. Gutierrez Jacques De Grève Steven Ballet |
author_sort |
Mathias Elsocht |
title |
Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors |
title_short |
Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors |
title_full |
Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors |
title_fullStr |
Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors |
title_full_unstemmed |
Structure–Activity Relationship (SAR) Study of Spautin-1 to Entail the Discovery of Novel NEK4 Inhibitors |
title_sort |
structure–activity relationship (sar) study of spautin-1 to entail the discovery of novel nek4 inhibitors |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2021-01-01 |
description |
Lung cancer is one of the most frequently diagnosed cancers accounting for the highest number of cancer-related deaths in the world. Despite significant progress including targeted therapies and immunotherapy, the treatment of advanced lung cancer remains challenging. Targeted therapies are highly efficacious at prolonging life, but not curative. In prior work we have identified Ubiquitin Specific Protease 13 (USP13) as a potential target to significantly enhance the efficacy of mutant EGFR inhibition. The current study aimed to develop lead molecules for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) by developing potent USP13 inhibitors initially starting from Spautin-1, the only available USP13 inhibitor. A SAR study was performed which revealed that increasing the chain length between the secondary amine and phenyl group and introducing a halogen capable of inducing a halogen bond at position 4’ of the phenyl group, dramatically increased the activity. However, we could not confirm the binding between Spautin-1 (or its analogues) and USP13 using isothermal titration calorimetry (ITC) or thermal shift assay (TSA) but do not exclude binding under physiological conditions. Nevertheless, we found that the anti-proliferative activity displayed by Spautin-1 towards EGFR-mutant NSCLC cells in vitro was at least partially associated with kinase inhibition. In this work, we present <i>N</i>-[2-(substituted-phenyl)ethyl]-6-fluoro-4-quinazolinamines as promising lead compounds for the treatment of NSCLC. These analogues are significantly more effective towards EGFR-mutant NSCLC cells than Spautin-1 and act as potent never in mitosis A related kinase 4 (NEK4) inhibitors (IC<sub>50</sub>~1 µM) with moderate selectivity over other kinases. |
topic |
non-small cell lung cancer USP13 NEK4 EGFR quinazolinamines |
url |
https://www.mdpi.com/1422-0067/22/2/635 |
work_keys_str_mv |
AT mathiaselsocht structureactivityrelationshipsarstudyofspautin1toentailthediscoveryofnovelnek4inhibitors AT philippegiron structureactivityrelationshipsarstudyofspautin1toentailthediscoveryofnovelnek4inhibitors AT lailamaes structureactivityrelationshipsarstudyofspautin1toentailthediscoveryofnovelnek4inhibitors AT wimversees structureactivityrelationshipsarstudyofspautin1toentailthediscoveryofnovelnek4inhibitors AT gustavojgutierrez structureactivityrelationshipsarstudyofspautin1toentailthediscoveryofnovelnek4inhibitors AT jacquesdegreve structureactivityrelationshipsarstudyofspautin1toentailthediscoveryofnovelnek4inhibitors AT stevenballet structureactivityrelationshipsarstudyofspautin1toentailthediscoveryofnovelnek4inhibitors |
_version_ |
1724341651982254080 |