1,721,092 research outputs found
Promises and drawbacks of targeting cell cycle kinases in cancer
No full textThe loss of ability in controlling cell cycle leads to aberrant cell growth and is a hallmark of cancer cells. Cell cycle regulation and progression mainly rely on protein phosphorylation events, therefore cell cycle kinases have long been viewed as potential targets for anticancer strategies. Consistently, cell cycle kinases are often dysregulated in different types of human cancer. Despite years of research and attempts directed at inhibiting cell cycle kinases, none of these approaches has been successfully translated to the clinic to halt tumorigenesis. Here, we review several currently pursued strategies and highlight both current challenges and some recent findings, which might help to develop new, better conceived therapeutic approaches based on cell-cycle kinase inhibition
Peptides or Small Molecules? Different Approaches to Develop More Effective CDK Inhibitors
No full textCell cycle regulation involves processes crucial to the survival of a cell, including the detection and repair of genetic damage as well as the prevention of uncontrolled cell division. The molecular events that control cell cycle are ordered and directional. Cyclins and cyclin-dependent kinases (CDKs), determine cell progression through the cycle ensuring the orderly coordination of cellular events. Alterations of cell cycle controllers are among the main causes of cancer onset. In the past decades many efforts have been made to develop kinase inhibitors that are able to modulate cyclin and CDK complexes, either by mimicking the function of natural CDK inhibitors, such as p21, p16 and p27, or by modulating the cyclin-CDK complexes or their targets directly. The great debate is whether to use peptides or small molecules. Peptides are more selective being derived by the linear protein sequences, indeed they should mimic the catalytic or the regulatory subunits of the cell cycle controller complexes, but on the other side they usually present poorer pharmacokinetic characteristics. In contrast, small molecules have better pharmacokinetic features but lower specificity because many protein kinases show high sequence similarity within the active site. The purpose of this review article is to provide an overview of the main classes of CDK inhibitors focusing on structure-activity relationship (SAR) studies and discussing the pharmacological and therapeutic implications
Targeting SRC family kinases in mesothelioma: Time to upgrade
Full text linkMalignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC and other SRC family kinase (SFK) members are frequently hyperactivated in many cancer types, including MM. Several works have indeed suggested that SFKs underlie MM cell proliferation, survival, motility, and invasion, overall affecting multiple oncogenic pathways. Consistently, SFK inhibitors effectively counteracted MM cancerous features at the preclinical level. Dasatinib, a multi-kinase inhibitor targeting SFKs, was also assessed in clinical trials either as second-line treatment for patients with unresectable MM or, more recently, as a neoadjuvant agent in patients with resectable MM. Here, we provide an overview of the molecular mechanisms implicating SFKs in MM progression and discuss possible strategies for a more successful clinical application of SFK inhibitors. Our aim is to stimulate discussion and further consideration of these agents in better designed preclinical and clinical studies to make the most of another class of powerful antitumoral drugs, which too often are lost in translation when applied to MM
Translating RB1 predictive value in clinical cancer therapy: Are we there yet?
No full textThe retinoblastoma RB1 gene has been identified in the 80s as the first tumor suppressor. RB1 loss of function, as well alterations in its pathway, occur in most human cancers and often have prognostic value. RB1 has a key role in restraining cell cycle entry and, along with its family members, regulates a myriad of cellular processes and affects cell response to a variety of stimuli, ultimately determining cell fate. Consistently, RB1 status is a crucial determinant of the cell response to antitumoral therapies, impacting on the outcome of both traditional and modern anti-cancer strategies, including precision medicine approaches, such as kinase inhibitors, and immunotherapy. Despite many efforts however, the predictive value of RB1 status in the clinical practice is still underused, mainly owing to the complexity of RB1 function, to differences depending on the cellular context and on the therapeutic strategies, and, not-lastly, to technical issues. Here, we provide an overview of studies analyzing the role of RB1 in response to conventional cytotoxic and cytostatic therapeutic agents in different cancer types, including hormone dependent ones. We also review RB1 predictive value in the response to the last generation CDK4/6 inhibitors, other kinase inhibitors, and immunotherapy and discuss new emerging non-canonical roles of RB1 that could impact on the response to antitumoral treatments
ATP-noncompetitive CDK inhibitors for cancer therapy: an overview
No full textINTRODUCTION:Cyclin-dependent kinases (CDKs) are the key drivers of cell cycle progression and are often deregulated in cancer, therefore, targeting CDKs has long been pursued as a therapeutic strategy to tackle cancer. Unfortunately, however, none of the first-generation CDK inhibitors has yielded the expected efficacy to be successfully translated to the clinic mostly because, by targeting the very conserved kinase ATP-binding site resulted to be poorly specific and quite toxic.
AREAS COVERED: Here, the authors review recent approaches aimed at developing more specific CDK inhibitors mostly through the aid of computational drug design studies and report various small molecules and peptides, which resulted in promising CDK ATP-noncompetitive inhibitors.
EXPERT OPINION: Despite few successes, these new approaches still need additional considerations to generate effective antitumoral agents. The authors discuss some of the hurdles to overcome for a successful clinical translation
Rb family proteins in gastric cancer
No full textGastric cancer is one of the most diffuse neoplastic pathologies in the world whose environmental and molecular causes, although deeply investigated, have not been completely clarified. Besides some well-established etiological factors, such as Helicobacter pylori and E-cadherin mutations, investigations on other possible causes gave contrasting results. Rb family proteins (including pRb/p105, pRb2/p130 and p107) are involved in cell cycle regulation and their function and/or expression is often lost in various kinds of tumours such as lung, bladder, breast and brain cancer. The consequences of RB inactivation in tumours can be very different depending on the context and the type of cancer. Recent evidence indicates that Rb status correlates with a different therapeutic response according to the tumour type and the therapeutic agent. Studies performed on Rb family proteins in gastrointestinal tract tumours suggest that these proteins have an important role in these cancer types. However, owing to contrasting results, further investigation is required to assess whether the expression of Rb family proteins can potentially be used as a prognostic or predictive factor in gastric cancer
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