CDK9 as a Valuable Target in Cancer: From Natural Compounds Inhibitors to Current Treatment in Pediatric Soft Tissue Sarcomas.

Matteo Cassandri,Antonello Mai,Rossella Fioravanti,Giada Del Baldo,Biagio De Angelis,Dante Rotili,Rossella Rota,Sergio Valente,Silvia Pomella

doi:10.3389/fphar.2020.01230

Matteo Cassandri, Antonello Mai + Show 7 more

Open Access

https://doi.org/10.3389/fphar.2020.01230

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Abstract

Cyclin-Dependent Kinases (CDKs) are well-known reliable targets for cancer treatment being often deregulated. Among them, since the transcription-associated CDK9 represents the sentry of cell transcriptional homeostasis, it can be a valuable target for managing cancers in which the transcriptional machinery is dysregulated by tumor-driver oncogenes. Here we give an overview of some natural compounds identified as CDK inhibitors with reported activity also against CDK9, that were taken as a model for the development of highly active synthetic anti-CDK9 agents. After, we summarize the data on CDK9 inhibition in a group of rare pediatric solid tumors such as rhabdomyosarcoma, Ewing’s sarcoma, synovial sarcoma and malignant rhabdoid tumors (soft tissue sarcomas), highlighting the more recent results in this field. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.

Highlights

The cyclin-dependent kinases (CDKs) family includes two main subgroups of kinases, those that mainly regulate cell cycle progression and those that control transcriptional processes (Roskoski, 2019; Chou et al, 2020)
While levels of cell cycle-associated CDKs do not change during the different phases of cell cycle progression, those of their cyclin partners oscillate in a proteasomal-dependent manner timely activating selected CDKs (Malumbres, 2014; Chou et al, 2020)
Since transcription-associated CDKs display conserved domains common to the cell cycle-associated ones, including the kinase domain, it has been suggested that cyclins/CDKs dimers can be evolutionary originated in more complex systems to strictly control more specialized cell functions

Summary

Introduction

The cyclin-dependent kinases (CDKs) family includes two main subgroups of kinases, those that mainly regulate cell cycle progression (including CDK1, CDK2, and CDK4/6) and those that control transcriptional processes (including CDK7, CDK8, CDK9, CDK12, and CDK13) (Roskoski, 2019; Chou et al, 2020). Unlike the compounds from which they derived, meriolins exerted anti-cancer effects in vivo and showed pro-apoptotic activity in vitro selectively inhibiting CDKs, including the CDK9-dependent phosphorylation RNA Pol II on Ser2, leading to consequent down-regulation of MCL1 and tumor cell death (Bettayeb et al, 2007).

Results

Conclusion