Cyclin Dependent Kinase as a Novel Therapeutic Target: An Endless Story

Abstract:: Cyclin Dependent Kinases (CDKs) are a family of enzymes that along with their Cyclin partners play a crucial role in cell cycle regulation at many biological functions such as proliferation, differentiation, DNA repair and apoptosis. Thus, they are tightly regulated by a vast of inhibitory and activating enzymes. Deregulation of these kinases’ activity either by amplification, overexpression or mutation of CDKs or Cyclins leads to uncontrolled proliferation of cancer cells. Hyperactivity of these kinases has been reported in wide variety of human cancers. Hence, CDKs has been established as one of the most attractive pharmacological targets in the development of promising anticancer drugs. The elucidated structural features and the well characterized molecular mechanisms of CDKs have been the guide in designing inhibitors to these kinases. Yet they remain a challenging therapeutic class as they share conserved structure similarity in their active site. Several inhibitors have been discovered from natural sources or identified through high through put screening and rational drug design approaches. Most of these inhibitors target the ATP binding pocket, so they suffer from many limitations. Now a growing number of ATP non-competitive peptides and small molecules have been reported.

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Carboplatin: molecular mechanisms of action associated with chemoresistance

Brazilian Journal of Pharmaceutical Sciences ◽

10.1590/s1984-82502014000400004 ◽

2014 ◽

Vol 50 (4) ◽

pp. 693-701 ◽

Cited By ~ 25

Author(s):

Graziele Fonseca de Sousa ◽

Samarina Rodrigues Wlodarczyk ◽

Gisele Monteiro

Keyword(s):

Molecular Mechanisms ◽

Therapeutic Strategies ◽

Mechanisms Of Action ◽

Rational Drug Design ◽

Full Potential ◽

Mechanisms Of Resistance ◽

Development Of Resistance ◽

Rational Drug ◽

Biochemical Mechanisms ◽

Tumor Types

Carboplatin is a derivative of cisplatin; it has a similar mechanism of action, but differs in terms of structure and toxicity. It was approved by the FDA in the 1980s and since then it has been widely used in the treatment of several tumor types. This agent is characterized by its ability to generate lesions in DNA through the formation of adducts with platinum, thereby inhibiting replication and transcription and leading to cell death. However, its use can lead to serious inconvenience arising from the development of resistance that some patients acquire during treatment, limiting the scope of its full potential. Currently, the biochemical mechanisms related to resistance are not precisely known. Therefore, knowledge of pathways associated with resistance caused by carboplatin exposure may provide valuable clues for more efficient rational drug design in platinum-based therapy and the development of new therapeutic strategies. In this narrative review, we discuss some of the known mechanisms of resistance to platinum-based drugs, especially carboplatin.

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Computational molecular modelling as a platform for a deeper understanding of protein dynamics and rational drug design

Biomedical Science and Engineering ◽

10.4081/bse.2019.87 ◽

2020 ◽

Author(s):

Gianvito Grasso ◽

Lorenzo Pallante ◽

Jack A. Tuszynski ◽

Umberto Morbiducci ◽

Marco A. Deriu

Keyword(s):

Molecular Modelling ◽

Molecular Level ◽

Structural Features ◽

Rational Drug Design ◽

Therapeutic Approaches ◽

Amyloidogenic Proteins ◽

Rational Drug ◽

Aggregation Inhibitors ◽

The Stability ◽

Toxicity Pathways

Elucidating structural features of protein aggregation at molecular level may provide novel opportunities for overarching therapeutic approaches such as blocking common aggregation-induced cellular toxicity pathways. In this context molecular modelling stimulates further research on amyloid aggregation modulators and modelling platforms can be used to test the efficiency of potential aggregation inhibitors aimed at destabilizing/reducing the stability of the amyloidogenic proteins

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Structure of the human gonadotropin-releasing hormone receptor GnRH1R reveals an unusual ligand binding mode

Nature Communications ◽

10.1038/s41467-020-19109-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Wei Yan ◽

Lin Cheng ◽

Wei Wang ◽

Chao Wu ◽

Xin Yang ◽

...

Keyword(s):

Ligand Binding ◽

Reproductive Function ◽

Binding Mode ◽

Structural Features ◽

Docking Studies ◽

Rational Drug Design ◽

Releasing Hormone ◽

Promising Therapeutic Target ◽

Rational Drug ◽

Main Regulator

Abstract Gonadotrophin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone, is the main regulator of the reproductive system, acting on gonadotropic cells by binding to the GnRH1 receptor (GnRH1R). The GnRH-GnRH1R system is a promising therapeutic target for maintaining reproductive function; to date, a number of ligands targeting GnRH1R for disease treatment are available on the market. Here, we report the crystal structure of GnRH1R bound to the small-molecule drug elagolix at 2.8 Å resolution. The structure reveals an interesting N-terminus that could co-occupy the enlarged orthosteric binding site together with elagolix. The unusual ligand binding mode was further investigated by structural analyses, functional assays and molecular docking studies. On the other hand, because of the unique characteristic of lacking a cytoplasmic C-terminal helix, GnRH1R exhibits different microswitch structural features from other class A GPCRs. In summary, this study provides insight into the ligand binding mode of GnRH1R and offers an atomic framework for rational drug design.

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Structural Features Underlying Selective Inhibition of GSK3β by Dibromocantharelline: Implications for Rational Drug Design

Chemical Biology & Drug Design ◽

10.1111/j.1747-0285.2010.01069.x ◽

2011 ◽

Vol 77 (3) ◽

pp. 199-205 ◽

Cited By ~ 15

Author(s):

Na Zhang ◽

Rugang Zhong ◽

Hong Yan ◽

Yongjun Jiang

Keyword(s):

Drug Design ◽

Selective Inhibition ◽

Structural Features ◽

Rational Drug Design ◽

Rational Drug

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The emerging importance of cyclin-dependent kinase inhibitors in the regulation of the plant cell cycle and related processesThis review is one of a selection of papers published in the Special Issue on Plant Cell Biology.

Canadian Journal of Botany ◽

10.1139/b06-043 ◽

2006 ◽

Vol 84 (4) ◽

pp. 640-650 ◽

Cited By ~ 22

Author(s):

Hong Wang ◽

Yongming Zhou ◽

Larry C. Fowke

Keyword(s):

Cell Cycle ◽

Cell Division ◽

Plant Cell ◽

Cell Biology ◽

Cell Cycle Regulation ◽

Cellular Localization ◽

Molecular Mechanisms ◽

Cdk Inhibitors ◽

Cyclin Dependent Kinase ◽

Cycle Regulation

The cell division cycle in plants as in other eukaryotes is controlled by the cyclin-dependent kinase (CDK). This CDK paradigm determines that developmental cues and environmental signals need to impinge on the CDK complex to affect the cell cycle. An important part of understanding cell cycle regulation is to understand how CDK is regulated by various factors. In addition, there are features that set the cell cycle regulation in plants apart from that in other eukaryotes such as animals. Our knowledge of the molecular mechanisms that underlie the differences is poor. A family of plant CDK inhibitor proteins has been identified. The plant CDK inhibitors share similarity with a family of animal CDK inhibitors in a small region, while most of the sequence and the structural layout of the plant CDK inhibitors are different from the animal counterparts. Studies of plant CDK inhibitors have been performed mostly with the CDK inhibitors from Arabidopsis called ICKs (also referred to as KRPs). ICKs interact with D-type cyclins and A-type CDK. Overexpression of ICKs has been shown to affect cell division, plant growth, and morphogenesis. Studies of ICKs have also provided insightful information on the control of endoreduplication in plants. These aspects as well as cellular localization and protein regulation of ICKs are reviewed.

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Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy

Journal of Personalized Medicine ◽

10.3390/jpm11111185 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1185

Author(s):

Matteo Costacurta ◽

Jackson He ◽

Philip E. Thompson ◽

Jake Shortt

Keyword(s):

Multiple Myeloma ◽

Small Molecules ◽

Molecular Mechanisms ◽

Rational Drug Design ◽

Genome Wide ◽

Rational Drug ◽

Anti Cancer ◽

Cellular Machinery ◽

Endogenous Substrates ◽

New Generation

Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of ‘neosubstrates’, Ikaros (IKZF1) and Aiolos (IKZF3), conveying concurrent antimyeloma activity and T-cell costimulation. There is now a greater understanding of physiological CRBN functions, including endogenous substrates and chaperone activity. CRISPR Cas9-based genome-wide screening has further elucidated the complex cellular machinery implicated in IMiD sensitivity, including IKZF1/3-independent mechanisms. New-generation IMiD derivatives with more potent anti-cancer properties—the CELMoDs (Cereblon E3 ligase modulators)—are now being evaluated. Rational drug design also allows ‘hijacking’ of CRL4CRBN utilising proteolysis targeting chimeras (PROTACs) to convey entirely distinct substrate repertoires. As all these chemotypes—thalidomide, IMiDs, CELMoDs and PROTACs—engage CRBN and modify its functions, we describe them here in aggregate as ‘CRBN-interacting small molecules’ (CISMs). In this review, we provide a contemporary summary of the biological consequences of CRBN modulation by CISMs. Detailed molecular insight into CRBN–CISM interactions now provides an opportunity to more effectively target previously elusive cancer dependencies, representing a new and powerful tool for the implementation of precision medicine.

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A New Oxadiazole-Based Topsentin Derivative Modulates Cyclin-Dependent Kinase 1 Expression and Exerts Cytotoxic Effects on Pancreatic Cancer Cells

Molecules ◽

10.3390/molecules27010019 ◽

2021 ◽

Vol 27 (1) ◽

pp. 19

Author(s):

Camilla Pecoraro ◽

Barbara Parrino ◽

Stella Cascioferro ◽

Adrian Puerta ◽

Amir Avan ◽

...

Keyword(s):

Cell Cycle Progression ◽

Binding Pocket ◽

Ductal Adenocarcinoma ◽

Pharmacokinetic Parameters ◽

Cyclin Dependent Kinase ◽

Cycle Progression ◽

Pancreatic Cancer Cells ◽

Pharmacological Targets ◽

Ic50 Values ◽

Hematological Tumors

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal form of cancer characterized by drug resistance, urging new therapeutic strategies. In recent years, protein kinases have emerged as promising pharmacological targets for the treatment of several solid and hematological tumors. Interestingly, cyclin-dependent kinase 1 (CDK1) is overexpressed in PDAC tissues and has been correlated to the aggressive nature of these tumors because of its key role in cell cycle progression and resistance to the induction of apoptosis. For these reasons, CDK1 is one of the main causes of chemoresistance, representing a promising pharmacological target. In this study, we report the synthesis of new 1,2,4-oxadiazole compounds and evaluate their ability to inhibit the cell growth of PATU-T, Hs766T, and HPAF-II cell lines and a primary PDAC cell culture (PDAC3). Compound 6b was the most active compound, with IC50 values ranging from 5.7 to 10.7 µM. Molecular docking of 6b into the active site of CDK1 showed the ability of the compound to interact effectively with the adenosine triphosphate binding pocket. Therefore, we assessed its ability to induce apoptosis (which increased 1.5- and 2-fold in PATU-T and PDAC3 cells, respectively) and to inhibit CDK1 expression, which was reduced to 45% in Hs766T. Lastly, compound 6b passed the ADME prediction, showing good pharmacokinetic parameters. These data demonstrate that 6b displays cytotoxic activity, induces apoptosis, and targets CDK1, supporting further studies for the development of similar compounds against PDAC.

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Inhibitors of cyclin-dependent kinases as new class of drugs in oncology. Achievements and development prospects in treatment of ER+ /HER 2- breast cancer

Medical alphabet ◽

10.33667/2078-5631-2019-1-10(385)-6-14 ◽

2019 ◽

Vol 1 (10) ◽

pp. 6-14

Author(s):

A. A. Vakhitova ◽

R. V. Orlova

Keyword(s):

Breast Cancer ◽

Molecular Mechanisms ◽

Metastatic Breast ◽

Cyclin Dependent Kinases ◽

New Class ◽

Hormone Sensitive ◽

Her 2 ◽

Cycle Regulation ◽

Development Prospects

The review is devoted to a new class of drugs - inhibitors of cy-clin-dependent kinases. The discovery of the genetic and molecular mechanisms of cell cycle regulation, and as a result, the emergence of CDK4 / 6 inhibitors was a breakthrough in the treatment of ER+ HER2- metastatic breast cancer and changed the paradigm of hormone therapy in this group of patients. We consider the current role of CDK4 / 6 inhibitors in treating patients with hormone-sensitive breast cancer, as well as the prospects for the future use of this class of drugs. The article presents the results of the main registration studies of the FDA-approved inhibitors of CDK4 / 6: palbocyclyb, ribocyclyb, abemocyclib; a comparative analysis of their efficacy and toxicity profile was carried out.

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Restriction of S-adenosylmethionine conformational freedom by knotted protein binding sites

10.1101/826248 ◽

2019 ◽

Cited By ~ 1

Author(s):

Agata P. Perlinska ◽

Adam Stasiulewicz ◽

Ewa K. Nawrocka ◽

Krzysztof Kazimierczuk ◽

Piotr Setny ◽

...

Keyword(s):

Binding Sites ◽

Protein Function ◽

Tight Binding ◽

Structural Features ◽

Rational Drug Design ◽

Conformational Space ◽

Nmr Studies ◽

Rational Drug ◽

Specific Proteins ◽

Conformational Freedom

AbstractS-adenosylmethionine (SAM) is one of the most important enzyme substrates. It is vital for the function of various proteins, including large group of methyltransferases (MTs). Intriguingly, some bacterial and eukaryotic MTs, while catalysing the same reaction, possess significantly different topologies, with the former being a knotted one. Here, we conducted a comprehensive analysis of SAM conformational space and factors that affect its vastness. We investigated SAM in two forms: free in water (via NMR studies and explicit solvent simulations) and bound to proteins (based on all data available in the PDB). We identified structural descriptors – angles which show the major differences in SAM conformation between unknotted and knotted methyltransferases. Moreover, we report that this is caused mainly by a characteristic for knotted MTs tight binding site formed by the knot and the presence of adenine-binding loop. Additionally, we elucidate conformational restrictions imposed on SAM molecules by other protein groups in comparison to conformational space in water.Author summaryThe topology of a folded polypeptide chain has great impact on the resulting protein function and its interaction with ligands. Interestingly, topological constraints appear to affect binding of one of the most ubiquitous substrates in the cell, S-adenosylmethionine (SAM), to its target proteins. Here, we demonstrate how binding sites of specific proteins restrict SAM conformational freedom in comparison to its unbound state, with a special interest in proteins with non-trivial topology, including an exciting group of knotted methyltransferases. Using a vast array of computational methods combined with NMR experiments, we identify key structural features of knotted methyltransferases that impose unorthodox SAM conformations. We compare them with the characteristics of standard, unknotted SAM binding proteins. These results are significant for understanding differences between analogous, yet topologically different enzymes, as well as for future rational drug design.

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