Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase

The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In...

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Autores principales:	Sandeep Rana, Jayapal Reddy Mallareddy, Sarbjit Singh, Lidia Boghean, Amarnath Natarajan
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	kinase CDK cancer PROTAC molecular glue Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/99d03c92392341989cb9e45c2edd63ef
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spelling	oai:doaj.org-article:99d03c92392341989cb9e45c2edd63ef2021-11-11T15:33:46ZInhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase10.3390/cancers132155062072-6694https://doaj.org/article/99d03c92392341989cb9e45c2edd63ef2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5506https://doaj.org/toc/2072-6694The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In this review, we will briefly inventory CDK inhibitors that are either part of over 30 active clinical trials or recruiting patients. The lack of selectivity among CDKs and dose-limiting toxicities are major challenges associated with the development of CDK inhibitors. Proteolysis Targeting Chimeras (PROTACs) and Molecular Glues have emerged as alternative therapeutic modalities to target proteins. PROTACs and Molecular glues utilize the cellular protein degradation machinery to destroy the target protein. PROTACs are heterobifunctional molecules that form a ternary complex with the target protein and E3-ligase by making two distinct small molecule–protein interactions. On the other hand, Molecular glues function by converting the target protein into a “<i>neo-substrate</i>” for an E3 ligase. Unlike small molecule inhibitors, preclinical studies with CDK targeted PROTACs have exhibited improved CDK selectivity. Moreover, the efficacy of PROTACs and molecular glues are not tied to the dose of these molecular entities but to the formation of the ternary complex. Here, we provide an overview of PROTACs and molecular glues that modulate CDK function as emerging therapeutic modalities.Sandeep RanaJayapal Reddy MallareddySarbjit SinghLidia BogheanAmarnath NatarajanMDPI AGarticlekinaseCDKcancerPROTACmolecular glueNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5506, p 5506 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	kinase CDK cancer PROTAC molecular glue Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	kinase CDK cancer PROTAC molecular glue Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Sandeep Rana Jayapal Reddy Mallareddy Sarbjit Singh Lidia Boghean Amarnath Natarajan Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
description	The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In this review, we will briefly inventory CDK inhibitors that are either part of over 30 active clinical trials or recruiting patients. The lack of selectivity among CDKs and dose-limiting toxicities are major challenges associated with the development of CDK inhibitors. Proteolysis Targeting Chimeras (PROTACs) and Molecular Glues have emerged as alternative therapeutic modalities to target proteins. PROTACs and Molecular glues utilize the cellular protein degradation machinery to destroy the target protein. PROTACs are heterobifunctional molecules that form a ternary complex with the target protein and E3-ligase by making two distinct small molecule–protein interactions. On the other hand, Molecular glues function by converting the target protein into a “<i>neo-substrate</i>” for an E3 ligase. Unlike small molecule inhibitors, preclinical studies with CDK targeted PROTACs have exhibited improved CDK selectivity. Moreover, the efficacy of PROTACs and molecular glues are not tied to the dose of these molecular entities but to the formation of the ternary complex. Here, we provide an overview of PROTACs and molecular glues that modulate CDK function as emerging therapeutic modalities.
format	article
author	Sandeep Rana Jayapal Reddy Mallareddy Sarbjit Singh Lidia Boghean Amarnath Natarajan
author_facet	Sandeep Rana Jayapal Reddy Mallareddy Sarbjit Singh Lidia Boghean Amarnath Natarajan
author_sort	Sandeep Rana
title	Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
title_short	Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
title_full	Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
title_fullStr	Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
title_full_unstemmed	Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
title_sort	inhibitors, protacs and molecular glues as diverse therapeutic modalities to target cyclin-dependent kinase
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/99d03c92392341989cb9e45c2edd63ef
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Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase

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