-
American Journal of Cancer Research 2021Dysregulated cell division, which leads to aberrant cell proliferation, is one of the key hallmarks of cancer. Therefore, therapeutic targets that block cell division... (Review)
Review
Dysregulated cell division, which leads to aberrant cell proliferation, is one of the key hallmarks of cancer. Therefore, therapeutic targets that block cell division would be effective for cancer treatment. Cell division is mainly controlled by a complex composed of cyclin and cyclin dependent kinases (CDKs). To date, the CDK inhibitors (CDKIs), specifically the ones that block the enzyme activity of CDK4 and CDK6 (CDK4/6), have been approved by FDA for the treatment of metastatic hormone receptor positive breast cancer. However, due to the non-selectivity and significant toxicity, most of the first generation CDK inhibitors (so called pan-CDK inhibitors that target several CDKs), have not been approved for clinical application. Despite this, great efforts and progress have been made to enable pan-CDK inhibitors application in the clinical setting. Notably, the development of combination therapy strategies in recent years has made it possible to reduce the toxicity and side effects of pan-CDK inhibitors. Thus, as a combination therapy approach, pan-CDK inhibitors regain great potential in clinical application. In this review, we introduced the CDK family members and discussed their major functions in cell cycle controlling. Then, we summarized the research progress regarding CDK inhibitors, especially those other than CDK4/6 inhibitors. We reviewed first-generation pan-CDKIs Flavopiridol and Roscovitine, and second-generation CDKIs Dinaciclib, P276-00, AT7519, TG02, Roniciclib, RGB-286638 by focusing on their developing stages, clinical trials and targeting cancers. The specific CDKIs, which targets to increase specificity and decrease the side effects, were also discussed. These CDKIs include CDK4/6, CDK7, CDK9, and CDK12/13 inhibitors. Finally, the efficacy and discrepancy of combination therapy with CDK inhibitors and PD1/PDL1 antibodies were analyzed, which might give insights into the development of promising strategy for cancer treatment.
PubMed: 34094661
DOI: No ID Found -
Current Opinion in Chemical Biology Oct 2022Transcription by RNA polymerase II (pol II) is regulated by kinases. In recent years, many selective and potent inhibitors of pol II transcription-associated kinases... (Review)
Review
Transcription by RNA polymerase II (pol II) is regulated by kinases. In recent years, many selective and potent inhibitors of pol II transcription-associated kinases have been developed, and these molecules have advanced understanding of kinase function in mammalian cells. Here, we focus on chemical inhibitors of the transcription-associated kinases CDK7, CDK8, CDK9, CDK12, CDK13, and CDK19. We provide a brief overview of the function of these kinases and common activation mechanisms. We then highlight the advantages of kinase inhibitors compared with other basic research methods, and describe the caveats associated with non-selective compounds (e.g. flavopiridol). We conclude with strategies and recommendations for implementation of chemical inhibitors for experimental analysis of transcription-associated kinases.
Topics: Animals; Cyclin-Dependent Kinases; Mammals; Phosphorylation; RNA Polymerase II
PubMed: 35926294
DOI: 10.1016/j.cbpa.2022.102186 -
Cell Chemical Biology Aug 2019The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear...
The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five different phenotypic and biochemical assays to compare approved inhibitors of cyclin-dependent kinases 4/6-collectively regarded as breakthroughs in the treatment of hormone receptor-positive breast cancer. We find that transcriptional, proteomic, and phenotypic changes induced by palbociclib, ribociclib, and abemaciclib differ significantly; abemaciclib in particular has advantageous activities partially overlapping those of alvocidib, an older polyselective CDK inhibitor. In cells and mice, abemaciclib inhibits kinases other than CDK4/6 including CDK2/cyclin A/E-implicated in resistance to CDK4/6 inhibition-and CDK1/cyclin B. The multifaceted experimental and computational approaches described here therefore uncover underappreciated differences in CDK4/6 inhibitor activities with potential importance in treating human patients.
Topics: Animals; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Mice; Mice, Nude; Polypharmacology; Protein Kinase Inhibitors; United States; United States Food and Drug Administration
PubMed: 31178407
DOI: 10.1016/j.chembiol.2019.05.005 -
Oncotarget Nov 2010Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy.... (Review)
Review
Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy. Nevertheless, refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis. Important risk factors are 17p deletion and/or mutation of TP53. For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved. Meanwhile we have to face also refractoriness to alemtuzumab. Importantly, the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL. The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor. Further B-cell antigens are targeted by lumiliximab (CD23), TRU-016 (CD37) and blinatumomab (CD19). Apart from monoclonal antibody therapies, a great number of small molecules are examined for the treatment of refractory and relapsed CLL. Most of these agents aim to overcome apoptosis resistance in CLL cells or influence the microenvironment. Typical targets are regulators of the cell cycle and antiapoptotic molecules like the members of the Bcl-2 family. Up to now the most promising agents appear to be flavopiridol and lenalidomide among others.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Drug Resistance, Neoplasm; Histone Deacetylase Inhibitors; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Survival Analysis; Therapies, Investigational; Vidarabine
PubMed: 21317446
DOI: 10.18632/oncotarget.184 -
Molecules (Basel, Switzerland) Nov 2023Flavopiridol is a flavone synthesized from the natural product rohitukine, which is derived from an Indian medicinal plant, namely . A deeper understanding of the... (Review)
Review
Flavopiridol is a flavone synthesized from the natural product rohitukine, which is derived from an Indian medicinal plant, namely . A deeper understanding of the biological mechanisms by which such molecules act may allow scientists to develop effective therapeutic strategies against a variety of life-threatening diseases, such as cancer, viruses, fungal infections, parasites, and neurodegenerative diseases. Mechanistic insight of flavopiridol reveals its potential for kinase inhibitory activity of CDKs (cyclin-dependent kinases) and other kinases, leading to the inhibition of various processes, including cell cycle progression, apoptosis, tumor proliferation, angiogenesis, tumor metastasis, and the inflammation process. The synthetic derivatives of flavopiridol have overcome a few demerits of its parent compound. Moreover, these derivatives have much improved CDK-inhibitory activity and therapeutic abilities for treating severe human diseases. It appears that flavopiridol has potential as a candidate for the formulation of an integrated strategy to combat and alleviate human diseases. This review article aims to unravel the potential therapeutic effectiveness of flavopiridol and its possible mechanism of action.
Topics: Humans; Flavonoids; Cyclin-Dependent Kinases; Phosphorylation; Neoplasms; Antineoplastic Agents; Apoptosis
PubMed: 38005250
DOI: 10.3390/molecules28227530 -
Leukemia & Lymphoma Oct 2013Abstract As the rational application of targeted therapies in cancer supplants traditional cytotoxic chemotherapy, there is an ever-greater need for a thorough... (Review)
Review
Abstract As the rational application of targeted therapies in cancer supplants traditional cytotoxic chemotherapy, there is an ever-greater need for a thorough understanding of the complex machinery of the cell and an application of this knowledge to the development of novel therapeutics and combinations of agents. Here, we review the current state of knowledge of the class of targeted agents known as cyclin-dependent kinase (CDK) inhibitors, with a focus on chronic lymphocytic leukemia (CLL). Flavopiridol (alvocidib) is the best studied of the CDK inhibitors, producing a dramatic cytotoxic effect in vitro and in vivo, with the principal limiting factor of acute tumor lysis. Unfortunately, flavopiridol has a narrow therapeutic window and is relatively non-selective with several off-target (i.e. non-CDK) effects, which prompted development of the second-generation CDK inhibitor dinaciclib. Dinaciclib appears to be both more potent and selective than flavopiridol, with at least an order of magnitude greater therapeutic index, and is currently in phase III clinical trials. In additional to flavopiridol and dinaciclib, we also review the current status of other members of this class, and provide commentary as to the future direction of combination therapy including CDK inhibitors.
Topics: Antineoplastic Agents; Cell Cycle; Clinical Trials as Topic; Cyclin-Dependent Kinases; Cyclins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Protein Kinase Inhibitors
PubMed: 23488658
DOI: 10.3109/10428194.2013.783911 -
Journal of Controlled Release :... May 2021For more than 30 years, treatment of acute myeloid leukemia (AML) has remained largely unchanged and reliant on chemotherapeutic drug combinations, specifically...
For more than 30 years, treatment of acute myeloid leukemia (AML) has remained largely unchanged and reliant on chemotherapeutic drug combinations, specifically cytarabine and daunorubicin (the 7 + 3 regimen). One broad spectrum drug, flavopiridol (also known as Alvocidib) has shown significant activity against AML through the inhibition of cyclin-dependent kinases. Flavopiridol is a semisynthetic flavonoid and our research team recently described methods to formulate another flavonoid, quercetin, through the ability of flavonoids to bind divalent metals. This method relies on use of copper-containing liposomes to enhance the apparent solubility of flavopiridol and to create formulations suitable for intravenous (i.v.) use. Similar to quercetin, flavopiridol is defined as an aqueous-insoluble compound (< 1 mg/mL in water) and this research sought to evaluate whether the copper-binding capabilities of flavopiridol could be used to prepare an injectable formulation that would exhibit enhanced exposure and improved efficacy. Flavopiridol powder was added directly to preformed copper-containing liposomes (DSPC:Chol or DSPC:DSPE-PEG2000) and the resulting formulations were characterized. Pharmacokinetic and efficacy studies were then conducted. The liposomal flavopiridol formulations were well-tolerated in mice following i.v. administration at a dose of 5 mg/kg with no apparent acute or chronic toxicities. In vivo pharmacokinetics of the optimized DSPC/DSPE-PEG2000 liposomal flavopiridol formulation demonstrated a 30-fold increase in AUC (0.804 μg-hr/mL versus 26.92 μg-hr/mL) compared to the free flavopiridol formulation. The resultant liposomal formulation also demonstrated significant therapeutic activity in MV4-11 and MOLM-13 subcutaneous AML models. Additional studies will be required to define whether formulation changes can be made to enhance flavopiridol retention in the selected composition. The results suggest that further increases in flavopiridol retention will result in improved therapeutic activity.
Topics: Animals; Cytarabine; Flavonoids; Leukemia, Myeloid, Acute; Liposomes; Mice; Piperidines
PubMed: 33798663
DOI: 10.1016/j.jconrel.2021.03.042 -
Blood Reviews Jul 2016Acute myeloid leukemia (AML) remains a challenge to both patients and clinicians. Despite improvements in our understanding of the disease, treatment has changed... (Review)
Review
Acute myeloid leukemia (AML) remains a challenge to both patients and clinicians. Despite improvements in our understanding of the disease, treatment has changed minimally and outcomes remain poor for the majority of patients. Within the last decade, there have been an increasing number of potential targets and pathways identified for development in AML. The classes of agents described in this review include but are not limited to epigenetic modifiers such as IDH inhibitors, BET inhibitors, and HDAC inhibitors as well as cell cycle and signaling inhibitors such as Aurora kinase inhibitors and CDK inhibitors. While the developments are encouraging, it is unlikely that targeting a single pathway will result in long-term disease control. Accordingly, we will also highlight potential rational partners for the novel agents described herein.
Topics: Antineoplastic Agents; Humans; Leukemia, Myeloid, Acute
PubMed: 26972558
DOI: 10.1016/j.blre.2016.02.001 -
Pharmaceuticals (Basel, Switzerland) Dec 2021Flavonoids are a group of natural products with a great structural diversity, widely distributed in plant kingdom. They play an important role in plant growth,... (Review)
Review
Flavonoids are a group of natural products with a great structural diversity, widely distributed in plant kingdom. They play an important role in plant growth, development and defense against aggressors. Flavonoids show a huge variety of biological activities such as antioxidant, anti-inflammatory, anti-mutagenic, antimicrobial and antitumor, being able to modulate a large diversity of cellular enzymatic activities. Among natural flavonoids, some classes comprise chiral molecules including flavanones, flavan-3-ols, isoflavanones, and rotenoids, which have one or more stereogenic centers. Interestingly, in some cases, individual compounds of enantiomeric pairs have shown different antitumor activity. In nature, these compounds are mainly biosynthesized as pure enantiomers. Nevertheless, they are often isolated as racemates, being necessary to carry out their chiral separation to perform enantioselectivity studies. Synthetic chiral flavonoids with promising antitumor activity have also been obtained using diverse synthetic approaches. In fact, several new chiral bioactive flavonoids have been synthesized by enantioselective synthesis. Particularly, flavopiridol was the first cyclin-dependent kinase (CDK) inhibitor which entered clinical trials. The chiral pool approaches using amino acid as chiral building blocks have also been reported to achieve small libraries of chrysin derivatives with more potent in vitro growth inhibitory effect than chrysin, reinforcing the importance of the introduction of chiral moieties to improve antitumor activity. In this work, a literature review of natural and synthetic chiral flavonoids with antitumor activity is reported for the first time.
PubMed: 34959668
DOI: 10.3390/ph14121267 -
Cancers Jan 2022Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired... (Review)
Review
Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors.
PubMed: 35053461
DOI: 10.3390/cancers14020293