The Relevance of Aurora Kinase Inhibition in Hematological Malignancies

2021 ◽  
Vol 1 (3) ◽  
pp. 111-126
Author(s):  
CAIO BEZERRA MACHADO ◽  
EMERSON LUCENA DA SILVA ◽  
BEATRIZ MARIA DIAS NOGUEIRA ◽  
JEAN BRENO SILVEIRA DA SILVA ◽  
MANOEL ODORICO DE MORAES FILHO ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Hematological Malignancies ◽  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Aurora Kinase ◽  
Aurora Kinases ◽  
The Past ◽  
Oncologic Patients

Aurora kinases are a family of serine/threonine protein kinases that play a central role in eukaryotic cell division. Overexpression of aurora kinases in cancer and their role as major regulators of the cell cycle quickly inspired the idea that their inhibition might be a potential pathway when treating oncologic patients. Over the past couple of decades, the search for designing and testing of molecules capable of inhibiting aurora activities fueled many pre-clinical and clinical studies. In this study, data from the past 10 years of in vitro and in vivo investigations, as well as clinical trials, utilizing aurora kinase inhibitors as therapeutics for hematological malignancies were compiled and discussed, aiming to highlight potential uses of these inhibitors as a novel monotherapy model or alongside conventional chemotherapies. While there is still much to be elucidated, it is clear that these kinases play a key role in oncogenesis, and their manageable toxicity and potentially synergistic effects still render them a focus of interest for future investigations in combinatorial clinical trials

Molecular characterization of neuroendocrine prostate cancer (NEPC) and identification of new drug targets.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 19-19 ◽  
Author(s):  
H. Beltran ◽  
D. Rickman ◽  
K. Park ◽  
A. Sboner ◽  
T. Macdonald ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Drug Targets ◽  
Kinase Activity ◽  
Aurora Kinase ◽  
Large Cohort ◽  
Small Subset ◽  
Aurora Kinases ◽  
New Drug

19 Background: NEPC is an aggressive variant of prostate cancer that can arise de novo or from existing prostate adenocarcinoma (PCA). We sought to better understand the molecular transformation of NEPC and identify new drug targets. Methods: We used Next Generation RNA sequencing and oligonucleotide arrays to profile 7 NEPC, 30 PCA, 5 benign prostate (BEN), and validated findings on tumors from a large cohort of patients (30 NEPC, 118 PCA, 30 BEN) using IHC and FISH. Functional studies were performed using NCI-H660 (NEPC), VCaP and LnCaP (PCA), RWPE (BEN). Results: ERG rearrangement was present in 47% of NEPC, but ERG protein expression was absent and corresponded directly with lack of AR expression. 936/25932 genes were differentially expressed in NEPC versus PCA (P<0.001). Aurora kinases (AURKA, AURKB) and N-myc (MYCN) were overexpressed in NEPC (P<0.001) and AURKA and MYCN amplified. Using IHC and FISH, we validated these findings on a large cohort and found majority (>80%) of NEPC showed Aurora overexpression, 35% had AURKA and MYCN amplification. A small subset of PCA (5%) and no BEN were positive. Transfection of MYCN induced AURKA expression and kinase activity in vitro, and MYCN or AURKA could induce expression of neuroendocrine (NE) markers (SYP, NSE). After validating NCI-H660 as model of NEPC, we observed dramatic and enhanced in vitro and in vivo sensitivity to the Aurora kinase inhibitor PHA-739358 in NCI-H660 compared to minimal to no effect in LnCaP and VCaP. Phospho-H3 expression, a downstream marker of Aurora kinase activity, was inhibited in the treated NCI-H660 and not in PCA. Notably, NE marker expression was also suppressed in the treated NCI-H660 xenografts, again supporting a role of Aurora kinase in modulating the NE phenotype. Conclusions: There is likely clonal origin of NEPC from PCA (with ERG fusion positivity seen in both), but ERG expression is limited to PCA and driven by AR signaling. We discovered significant overexpression and gene amplification of Aurora kinases and N-myc in NEPC and a small subset of PCA, and evidence that that they cooperate and induce a NE phenotype in prostate cells. In vitro and in vivo data confirms that these are novel drug targets for NEPC. No significant financial relationships to disclose.

scholarly journals Vandetanib Reduces Inflammatory Cytokines and Ameliorates COVID-19 in Infected Mice

2021 ◽  
Author(s):  
Ana C. Puhl ◽  
Giovanni F. Gomes ◽  
Samara Damasceno ◽  
Ethan J. Fritch ◽  
James A. Levi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Kinase Inhibitors ◽  
Hepatitis Virus ◽  
Growth Factor Receptor ◽  
Murine Hepatitis Virus ◽  
Epidermal Growth ◽  
Endothelial Growth Factor

The portfolio of SARS-CoV-2 small molecule drugs is currently limited to a handful that are either approved (remdesivir), emergency approved (dexamethasone, baricitinib) or in advanced clinical trials. We have tested 45 FDA-approved kinase inhibitors in vitro against murine hepatitis virus (MHV) as a model of SARS-CoV-2 replication and identified 12 showing inhibition in the delayed brain tumor (DBT) cell line. Vandetanib, which targets the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), and the RET-tyrosine kinase showed the most promising results on inhibition versus toxic effect on SARS-CoV-2-infected Caco-2 and A549-hACE2 cells (IC50 0.79 uM) while also showing a reduction of > 3 log TCID50/mL for HCoV-229E. The in vivo efficacy of vandetanib was assessed in a mouse model of SARS-CoV-2 infection and statistically significantly reduced the levels of IL-6, IL-10, TNF-a;, and mitigated inflammatory cell infiltrates in the lungs of infected animals but did not reduce viral load. Vandetanib rescued the decreased IFN-1b; caused by SARS-CoV-2 infection in mice to levels similar to that in uninfected animals. Our results indicate that the FDA-approved vandetanib is a potential therapeutic candidate for COVID-19 positioned for follow up in clinical trials either alone or in combination with other drugs to address the cytokine storm associated with this viral infection.

STAT5 and STAT5 Inhibitors in Hematological Malignancies

2020 ◽  
Vol 19 (17) ◽  
pp. 2036-2046
Author(s):  
Manlio Tolomeo ◽  
Maria Meli ◽  
Stefania Grimaudo
Keyword(s):  
Clinical Trials ◽  
Stem Cell ◽  
Hematological Malignancies ◽  
Kinase Inhibitors ◽  
Myeloproliferative Disorders ◽  
Main Role ◽  
Cellular Functions ◽  
Hematopoietic Stem ◽  
Immunological Responses

The JAK-STAT pathway is an important physiologic regulator of different cellular functions including proliferation, apoptosis, differentiation, and immunological responses. Out of six different STAT proteins, STAT5 plays its main role in hematopoiesis and constitutive STAT5 activation seems to be a key event in the pathogenesis of several hematological malignancies. This has led many researchers to develop compounds capable of inhibiting STAT5 activation or interfering with its functions. Several anti-STAT5 molecules have shown potent STAT5 inhibitory activity in vitro. However, compared to the large amount of clinical studies with JAK inhibitors that are currently widely used in the clinics to treat myeloproliferative disorders, the clinical trials with STAT5 inhibitors are very limited. At present, a few STAT5 inhibitors are in phase I or II clinical trials for the treatment of leukemias and graft vs host disease. These studies seem to indicate that such compounds could be well tolerated and useful in reducing the occurrence of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia. Of interest, STAT5 seems to play an important role in the regulation of hematopoietic stem cell self-renewal suggesting that combination therapies including STAT5 inhibitors can erode the cancer stem cell pool and possibly open the way for the complete cancer eradication. In this review, we discuss the implication of STAT5 in hematological malignancies and the results obtained with the novel STAT5 inhibitors.

scholarly journals An In Vitro Enrichment Strategy for Formulating Synergistic Synbiotics

2019 ◽  
Vol 85 (16) ◽  
Author(s):  
Car Reen Kok ◽  
David Fabian Gomez Quintero ◽  
Clement Niyirora ◽  
Devin Rose ◽  
Amanda Li ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Synergistic Effects ◽  
Bifidobacterium Longum ◽  
High Rate ◽  
Host Responses ◽  
Ecological Niches ◽  
Bacterial Populations ◽  
Content Type

ABSTRACT Research on the role of diet on gut and systemic health has led to considerable interest toward identifying novel therapeutic modulators of the gut microbiome, including the use of prebiotics and probiotics. However, various host responses have often been reported among many clinical trials. This is in part due to competitive exclusion as a result of the absence of ecological niches as well as host-mediated constraints via colonization resistance. In this research, we developed a novel in vitro enrichment (IVE) method for isolating autochthonous strains that can function as synergistic synbiotics and overcome these constraints. The method relied on stepwise in vitro fecal fermentations to enrich for and isolate Bifidobacterium strains that ferment the prebiotic xylooligosaccharide (XOS). We subsequently isolated Bifidobacterium longum subsp. longum CR15 and then tested its establishment in 20 unique fecal samples with or without XOS. The strain was established in up to 18 samples but only in the presence of XOS. Our findings revealed that the IVE method is suitable for isolating potential synergistic probiotic strains that possess the genetic and biochemical ability to ferment specific prebiotic substrates. The IVE method can be used as an initial high-throughput screen for probiotic selection and isolation prior to further characterization and in vivo tests. IMPORTANCE This study describes an in vitro enrichment method to formulate synergistic synbiotics that have potential for establishing autochthonous strains across multiple individuals. The rationale for this approach—that the chance of survival of a bacterial strain is improved by providing it with its required resources—is based on classic ecological theory. From these experiments, a human-derived strain, Bifidobacterium longum subsp. longum CR15, was identified as a xylooligosaccharide (XOS) fermenter in fecal environments and displayed synergistic effects in vitro. The high rate of strain establishment observed in this study provides a basis for using synergistic synbiotics to overcome the responder/nonresponder phenomenon that occurs frequently in clinical trials with probiotic and prebiotic interventions. In addition, this approach can be applied in other protocols that require enrichment of specific bacterial populations prior to strain isolation.

scholarly journals Emerging multitarget tyrosine kinase inhibitors in the treatment of neuroendocrine neoplasms

2018 ◽  
Vol 25 (9) ◽  
pp. R453-R466 ◽  
Author(s):  
Federica Grillo ◽  
Tullio Florio ◽  
Francesco Ferraù ◽  
Elda Kara ◽  
Giuseppe Fanciulli ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Neuroendocrine Cells ◽  
Neuroendocrine Neoplasms ◽  
Systematic Analysis ◽  
Clinical Trial Registries

In the last few years, the therapeutic approach for neuroendocrine neoplasms (NENs) has changed dramatically following the approval of several novel targeted treatments. The multitarget tyrosine kinase inhibitor (MTKI), sunitinib malate, has been approved by Regulatory Agencies in pancreatic NENs. The MTKI class, however, includes several other molecules (approved for other conditions), which are currently being studied in NENs. An in-depth review on the studies published on the MTKIs in neuroendocrine tumors such as axitinib, cabozantinib, famitinib, lenvatinib, nintedanib, pazopanib, sorafenib and sulfatinib was performed. Furthermore, we extensively searched on the Clinical Trial Registries databases worldwide, in order to collect information on the ongoing clinical trials related to this topic. Our systematic analysis on emerging MTKIs in the treatment of gastroenteropancreatic and lung NENs identifiesin vitroandin vivostudies, which demonstrate anti-tumor activity of diverse MTKIs on neuroendocrine cells and tumors. Moreover, for the first time in the literature, we report an updated view concerning the upcoming clinical trials in this field: presently, phase I, II and III clinical trials are ongoing and will include, overall, a staggering 1667 patients. This fervid activity underlines the increasing interest of the scientific community in the use of emerging MTKIs in NEN treatment.

Potential Pharmacological Inhibitors of Pim Kinase Under Clinical Trials

2018 ◽  
Vol 18 (8) ◽  
pp. 1100-1114 ◽  
Author(s):  
Gomathi P. Jeyapal ◽  
Moola J.N. Chandrasekar ◽  
Rajendiran Krishnasamy ◽  
Jubie Selvaraj ◽  
Manal Mohammad ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Human Cancer ◽  
Binding Pocket ◽  
Malignant Cell ◽  
Pim Kinases

Pim kinases, also known as Serine/Threonine kinases, are intensively studied protein drug targets in cancer research. They play crucial role in the regulation of signal transduction cascades that promote cell survival, proliferation and drug resistance. Pim kinases are overexpressed in several hematopoietic and solid tumors and support in vitro/in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. Pim kinases do not have an identified regulatory domain, as they are constitutively active. They appear to be critical downstream effectors of a number of oncoproteins. When overexpressed, they mediate drug resistance to agents such as Rapamycin. X-ray crystallographic studies reveal that unlike other kinases, Pim kinases have a hinge region, which forms a unique binding pocket for ATP, offering a target for a large number of potent small-molecule Pim kinase inhibitors. Combination therapy of Pim kinase inhibitors with chemotherapeutic and other kinase modulators seems to produce an additive cytotoxic effect in cancer cells. Though clinical trials have been carried out on the first Pim inhibitory agent, SGI-1776, no concept data could be generated due to its early withdrawal. However, it has helped in accelerating the discovery of several novel Pim inhibitors in recent years. Current research on Pim kinase is expected to lead to a new generation of potent Pim kinase inhibitors with appropriate pharmacological profiles suitable for human cancer therapy in the near future. Herein, we review the synthetic route and mechanistical studies of Pim kinase inhibitors which are currently in human trials.

Dual Inhibition of Aurora and FLT3 Kinases by CCT137690: A Novel Treatment Strategy Against FLT3-ITD Positive AML In Vitro and In Vivo

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3289-3289 ◽  
Author(s):  
Andrew S Moore ◽  
Amir Faisal ◽  
Vassilios Bavetsias ◽  
Chongbo Sun ◽  
Butrus Atrash ◽  
...  
Keyword(s):  
Cancer Research ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Aurora B ◽  
Aurora A ◽  
Aurora Kinases ◽  
Flt3 Inhibitor ◽  
Dual Inhibition

Abstract Abstract 3289 The Aurora kinases are a family of serine-threonine kinases that play key roles in different stages of mitosis. Over-expression of Aurora kinases has been demonstrated in a range of malignancies including leukemia. Aurora kinase inhibitors are emerging as promising agents in the treatment of acute myeloid leukemia (AML) with a number of compounds currently being assessed in clinical trials (Moore AS et al, Leukemia 2010). CCT137690, an imidazo[4,5-b]pyridine derivative discovered at our Institute, is an orally bioavailable, potent, pan-Aurora and FLT3 inhibitor with low nanomolar IC50 values against Aurora A (15 nM), Aurora B (25 nM), Aurora C (19 nM), and FLT3 (<0.5 nM) kinases. CCT137690 showed in vitro and in vivo activity in human colon cancer cell lines and xenograft models (Bavetsias V et al, J Med Chem 2010). Here we report the in vitro and in vivo activity of CCT137690 in FLT3-ITD positive AML. In vitro, the FLT3-ITD positive cell lines MV-4-11 and MOLM-13 are particularly sensitive with GI50 values less than 50 nM. Cellular assays demonstrate that CCT137690 inhibits autophosphorylation of Aurora A, Aurora B and Aurora C kinases and phosphorylation of histone H3, a direct target of Aurora B kinase. CCT137690 also inhibits autophosphorylation of FLT3 and phosphorylation of its downstream targets STAT5 and p44/42 MAPK (Erk1/2). Dual inhibition of Aurora and FLT3 kinases in FLT3-ITD positive AML with CCT137690 induces apoptosis and results in a unique cell cycle profile with cells accumulating in G2/M, whilst selective FLT3 inhibition with MLN518 resulted in G1/S arrest. When given orally to athymic mice, CCT137690 achieved target modulation and potently inhibited the growth of subcutaneous MOLM-13 xenografts, with no obvious toxicity or loss of body weight. Inhibition of MOLM-13 xenograft growth was more pronounced with CCT137690 compared to the selective FLT3 inhibitor MLN518, suggesting that dual inhibition of Aurora and FLT3 kinases may have advantages compared to selective FLT3 inhibition alone. The potent preclinical activity of CCT137690 in FLT3-ITD positive AML models supports the growing body of evidence that dual pan-Aurora and FLT3 kinase inhibitors may be of benefit in the high-risk group of patients with FLT3-ITD positive AML. Disclosures: Moore: The Institute of Cancer Research: Employment, The Institute of Cancer Research (ICR) has a commercial interest in drug development programs. Authors employed by ICR are subject to a Rewards to Inventors Scheme, which may reward contributors to a program that is subsequently licensed. Faisal:The Institute of Cancer Research: Employment. Bavetsias:The Institute of Cancer Research: Employment. Sun:The Institute of Cancer Research: Employment. Atrash:The Institute of Cancer Research: Employment. Valenti:The Institute of Cancer Research: Employment. de Haven Brandon:The Institute of Cancer Research: Employment. Avery:The Institute of Cancer Research: Employment. Raynaud:The Institute of Cancer Research: Employment. Workman:The Institute of Cancer Research: Employment. Pearson:The Institute of Cancer Research: Employment. Blagg:The Institute of Cancer Research: Employment. Eccles:The Institute of Cancer Research: Employment. Linardopoulos:The Institute of Cancer Research: Employment.

scholarly journals Novel Pan-Pim Kinase Inhibitors With Imidazopyridazine and Thiazolidinedione Structure Exert Potent Antitumor Activities

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuichi Sawaguchi ◽  
Ryuta Yamazaki ◽  
Yukiko Nishiyama ◽  
Masayuki Mae ◽  
Atsuhiro Abe ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Hematological Malignancies ◽  
Kinase Inhibitors ◽  
Xenograft Model ◽  
Cancer Cell Lines ◽  
Antitumor Activities ◽  
Pim Kinases

Pim kinases are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Here in this study, we investigated the preclinical profile of novel pan-Pim kinase inhibitors with imidazopyridazine and thiazolidinedione structure. Imidazopyridazine-thiazolidinediones inhibited activities of Pim kinases with IC50 values of tens to hundreds nanomolar. With YPC-21440 and/or YPC-21817, which exhibited especially high inhibitory activities against Pim kinases, we investigated in vitro and in vivo activities of imidazopyridazine-thiazolidinediones. In silico analysis of binding mode of YPC-21440 and Pim kinases revealed that it directly bound to ATP-binding pockets of Pim kinases. In the kinase panel tested, YPC-21440 and YPC-21817 were highly specific to Pim kinases. These compounds exerted antiproliferative activities against various cancer cell lines derived from hematological malignancies and solid carcinomas. Furthermore, they suppressed phosphorylation of Pim kinase substrates, arrested cell cycle at the G1 phase, and induced apoptosis in cultured cancer cells. In tumor xenograft models, YPC-21440 methanesulfonate and YPC-21817 methanesulfonate exerted antitumor activities. Furthermore, pharmacodynamic analysis with a xenograft model suggested that YPC-21817 methanesulfonate inhibited Pim kinases in tumors. In conclusion, our data revealed that imidazopyridazine-thiazolidinediones are novel Pim kinases inhibitors, effective on various types of cancer cell lines both in vitro and in vivo.

Approach in improving potency and selectivity of kinase inhibitors: Allosteric kinase inhibitors

2020 ◽  
Vol 21 ◽  
Author(s):  
Shangfei Wei ◽  
Tianming Zhao ◽  
Jie Wang ◽  
Xin Zhai
Keyword(s):  
Protein Interactions ◽  
Kinase Inhibitors ◽  
Binding Modes ◽  
Allosteric Inhibitors ◽  
Wide Range ◽  
Allosteric Sites ◽  
Protein Functions ◽  
Regulate Protein

: Allostery is an efficient and particular regulatory mechanism to regulate protein functions. Different from conserved orthosteric sites, allosteric sites have distinctive functional mechanism to form the complex regulatory network. In drug discovery, kinase inhibitors targeting the allosteric pockets have received extensive attention for the advantages of high selectivity and low toxicity. The approval of trametinib as the first allosteric inhibitor validated that allosteric inhibitors could be used as effective therapeutic drugs for treatment of diseases. To date, a wide range of allosteric inhibitors have been identified. In this perspective, we outline different binding modes and potential advantages of allosteric inhibitors. In the meantime, the research processes of typical and novel allosteric inhibitors are described briefly in terms of structureactivity relationships, ligand-protein interactions and in vitro and in vivo activity. Additionally, challenges as well as opportunities are presented.

Modulation of Matrix Metalloproteinases by Plant-Derived Products

2020 ◽  
Vol 20 ◽  
Author(s):  
Nur Najmi Mohamad Anuar ◽  
Nurul Iman Natasya Zulkafali ◽  
Azizah Ugusman
Keyword(s):  
Clinical Trials ◽  
Natural Products ◽  
Matrix Metalloproteinases ◽  
Animal Studies ◽  
Current Knowledge ◽  
In Vitro Models ◽  
In Vivo Studies ◽  
Extracellular Matrix Components

: Matrix metalloproteinases (MMPs) are a group of zinc-dependent metallo-endopeptidase that are responsible towards the degradation, repair and remodelling of extracellular matrix components. MMPs play an important role in maintaining a normal physiological function and preventing diseases such as cancer and cardiovascular diseases. Natural products derived from plants have been used as traditional medicine for centuries. Its active compounds, such as catechin, resveratrol and quercetin, are suggested to play an important role as MMPs inhibitors, thereby opening new insights into their applications in many fields, such as pharmaceutical, cosmetic and food industries. This review summarises the current knowledge on plant-derived natural products with MMP-modulating activities. Most of the reviewed plant-derived products exhibit an inhibitory activity on MMPs. Amongst MMPs, MMP-2 and MMP-9 are the most studied. The expression of MMPs is inhibited through respective signalling pathways, such as MAPK, NF-κB and PI3 kinase pathways, which contribute to the reduction in cancer cell behaviours, such as proliferation and migration. Most studies have employed in vitro models, but a limited number of animal studies and clinical trials have been conducted. Even though plant-derived products show promising results in modulating MMPs, more in vivo studies and clinical trials are needed to support their therapeutic applications in the future.

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