Poor therapeutic outcomes and serious side effects, together with acquired resistance to multiple drugs, are common problems of current cancer therapies. Therefore, there is an urgent need for new cancer-targeted drugs, which has led (inter alia) to the development of molecules that can specifically inhibit cyclin-dependent kinases (CDKs). In addition to their cell cycle regulatory functions, CDKs, especially CDK7 and CDK9, play important roles in the regulation of RNA polymerase II-mediated transcription. Here, we report on progress in the preclinical development of CDK inhibitors and their anticancer activities. Special attention is paid to the action mechanisms of the pan-specific CDK inhibitors flavopiridol and roscovitine, which have already entered phase II clinical trials as treatments for various tumours. The links between their ability to inhibit transcription and sensitisation of some types of cancer to apoptosis, mechanisms leading to p53 activation, and their synergistic cooperation with common DNA damaging drugs are also discussed. It has been demonstrated that drug-resistant cancer cells can arise during therapeutic application of small molecule protein kinase inhibitors. Clinical resistance to CDK inhibitors has not yet been described, but by comparing CDKs to other kinases, and CDK inhibitors to other clinically used protein kinase inhibitors, we also discuss possible mechanisms that could lead to resistance to CDK inhibitors.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• chemorezistence MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• inhibitory enzymů farmakologie   terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   MeSH
• preklinické hodnocení léčiv MeSH
• racionální návrh léčiv MeSH
• systémy cílené aplikace léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• antitumorózní látky MeSH
• cyklin-dependentní kinasy * antagonisté a inhibitory   chemie   MeSH
• lidé MeSH
• puriny * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Roscovitine is a synthetic inhibitor of cyclin-dependent kinases that is currently undergoing clinical trials as a candidate drug for some oncological indications. Its discovery prompted many research teams to further optimize its structure or to initiate their own related but independent studies. This article reviews known roscovitine bioisosteres that have been prepared as CDK inhibitors using different core heterocycles. The individual bioisostere types have been described and explored to a different extent, which complicates direct comparisons of their biochemical activity - only six direct analogs containing different purine bioisosteres have been prepared and evaluated side by side with roscovitine. Only four types of bioisosteres have demonstrated improved biological properties, namely pyrazolo[ 1,5-a]-1,3,5-triazines, pyrazolo[1,5-a]pyrimidines, pyrazolo[1,5-a]pyridines and pyrazolo[4,3-d]pyrimidines.

• MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• heterocyklické sloučeniny chemie   farmakologie   MeSH
• inhibitory proteinkinas chemie   farmakologie   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   MeSH
• puriny chemie   farmakologie   MeSH
• racionální návrh léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

INTRODUCTION: Cyclin-dependent kinase 7 (CDK7) is a member of the CDK family of serine/threonine protein kinases and participates in the regulation of the cell cycle and mRNA transcription. CDK7 is emerging as a possible drug target in oncology and six exciting drug candidates have already undergone early evaluation in clinical trials. AREAS COVERED: This review examines CDK7 inhibitors as anticancer drugs reported in patents published in the online databases of the World Intellectual Property Organization and European Patent Office in the 2018-2022 period. This review provides an overview of available inhibitors, including their chemical structures, biochemical profile and stage of development. EXPERT OPINION: Small-molecule CDK7 inhibitors represent attractive pharmacological modalities for the treatment of various cancer types. Highly potent and selective inhibitors have been discovered and many of them show promising results in several preclinical cancer models. Developed compounds act on the kinase by various mechanisms, including traditional ATP competition, irreversible binding to tractable cysteine 312 outside the active site of CDK7, and induced protein degradation by proteolysis targeting chimeras. Ongoing preclinical research and clinical trials should reveal which strategy will provide the highest benefits.

• MeSH
• cyklin-dependentní kinasy genetika   MeSH
• inhibitory proteinkinas farmakologie   chemie   MeSH
• kinasa aktivující cyklin dependentní kinasy * MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• patenty jako téma MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Inhibitors of cyclin-dependent kinases (CDKs) undergoing clinical trials as anticancer agents usually target several CDKs in cells. Some of them are also able to increase cellular levels of p53 protein and to activate p53-regulated transcription. To define the role of p53 in the anticancer effect of selective CDK inhibitors, two related compounds roscovitine and olomoucine II were studied. Roscovitine differs functionally from its congener olomoucine II only in the selectivity towards transcriptional CDK9. Action of both compounds on proliferation, cell-cycle progression, and apoptosis was examined in RPMI-8226 cells expressing the temperature-sensitive mutant of p53 and in MCF-7 cells with wild-type p53. Both compounds blocked proliferation, decreased phosphorylation of RNA polymerase II, downregulated antiapoptotic protein Mcl-1 in both cell lines in a dose-dependent manner, and also activated p53 in MCF-7 cells. Moreover, we showed that the anticancer efficiency of CDK inhibitors was enhanced by active p53 in RPMI-8226 cells kept at permissive temperature, where downregulation of Mcl-1, fragmentation of PARP-1, and increased caspase-3 activity was detected with lower doses of the compounds. The results confirm that functional p53 protein may enhance the anticancer activity of roscovitine that could be beneficial for anticancer therapy.

• MeSH
• antitumorózní látky farmakologie   MeSH
• buněčná smrt MeSH
• buněčný cyklus MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   metabolismus   MeSH
• fosforylace MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kaspasy metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• proliferace buněk MeSH
• puriny farmakologie   MeSH
• RNA-polymerasa II metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

3,5,7-Trisubstituted pyrazolo[4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine (24) at 1.7 Å resolution, confirming the competitive mode of inhibition. Biochemical and cellular assays in lymphoma cell lines confirmed the expected mechanism of action through dephosphorylation of retinoblastoma protein and RNA polymerase II, leading to induction of apoptosis. Importantly, we also revealed an interesting ability of compound 24 to induce proteasome-dependent degradation of cyclin K both in vitro and in a patient-derived xenograft in vivo. We propose that 24 has a dual mechanism of action, acting as a kinase inhibitor and as a molecular glue inducing an interaction between CDK12 and DDB1 that leads to polyubiquitination of cyclin K and its subsequent degradation.

• MeSH
• antitumorózní látky * chemie   farmakologie   MeSH
• cyklin-dependentní kinasa 2 MeSH
• cyklin-dependentní kinasy * MeSH
• cykliny metabolismus   MeSH
• inhibitory proteinkinas chemie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• pyrimidiny chemie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

INTRODUCTION: Cell cycle deregulation is a common characteristic of cancer cells. Progression through the cell cycle is controlled by enzymes known as cyclin-dependent kinases (CDKs), whose activity can be upregulated by a wide range of molecular mechanisms. Based on these observations, small molecule CDK inhibitors are being developed as potential cancer therapeutics. Some of these compounds have entered Phase III clinical trials and one of them, palbociclib, recently received accelerated approval from the FDA. However, the complexity of CDK biology and the undesired side effects of the existing inhibitors mean that the hunt for new CDK-targeting drug candidates continues. AREAS COVERED: This article reviews patent applications related to small molecule CDK inhibitors published between 2009 and 2014. EXPERT OPINION: Clinical trials with pan-specific inhibitors have generally yielded unambiguously positive outcomes. However, better results have been achieved with highly specific inhibitors of CDK4/CDK6. This may be due to several factors and has generated considerable interest in the discovery of new mono-specific CDK inhibitors. The development of such compounds is challenging because all CDKs have very similar active sites. Aside from this issue of selectivity, another key challenge is the identification of patients who will benefit from specific therapies.

• MeSH
• antitumorózní látky škodlivé účinky   farmakologie   MeSH
• cílená molekulární terapie MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• inhibitory proteinkinas škodlivé účinky   farmakologie   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   MeSH
• patenty jako téma MeSH
• racionální návrh léčiv MeSH
• schvalování léčiv MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• antitumorózní látky chemie   MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• finanční podpora výzkumu jako téma MeSH
• lidé MeSH
• pyrazoly farmakologie   chemie   MeSH
• pyrimidiny farmakologie   chemie   MeSH
• Check Tag
• lidé MeSH

Deregulation of cyclin-dependent kinases (CDKs) has been associated with many cancer types and has evoked an interest in chemical inhibitors with possible therapeutic benefit. While most known inhibitors display broad selectivity towards multiple CDKs, recent work highlights CDK9 as the critical target responsible for the anticancer activity of clinically evaluated drugs. In this review, we discuss recent findings provided by structural biologists that may allow further development of highly specific inhibitors of CDK9 towards applications in cancer therapy. We also highlight the role of CDK9 in inflammatory processes and diseases.

• MeSH
• antitumorózní látky farmakologie   MeSH
• cyklin-dependentní kinasa 9 antagonisté a inhibitory   metabolismus   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• nádory farmakoterapie   enzymologie   MeSH
• racionální návrh léčiv MeSH
• systémy cílené aplikace léků MeSH
• zánět enzymologie   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• Klíčová slova
• BOHEMIN, OLOMOUCIN,
• MeSH
• antitumorózní látky farmakokinetika   MeSH
• buněčná diferenciace MeSH
• cyklin-dependentní kinasy antagonisté a inhibitory   MeSH
• puriny analogy a deriváty   farmakokinetika   MeSH
• techniky in vitro MeSH
• Publikační typ
• kongresy MeSH