scholarly journals Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Zijian Zhang ◽  
Deshun Zeng ◽  
Wei Zhang ◽  
Ailin Chen ◽  
Jie Lei ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Kinase Inhibitors ◽  
Tumor Regression ◽  
Aurora Kinase ◽  
Phase Iii ◽  
Therapeutic Effects ◽  
Combination Regimen ◽  
Mitotic Kinase ◽  
Mechanistic Investigation

AbstractUncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.

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

Combination of Antiangiogenic Therapy With Other Anticancer Therapies: Results, Challenges, and Open Questions

2005 ◽  
Vol 23 (6) ◽  
pp. 1295-1311 ◽  
Author(s):  
Giampietro Gasparini ◽  
Raffaele Longo ◽  
Massimo Fanelli ◽  
Beverly A. Teicher
Keyword(s):  
Tumor Growth ◽  
Clinical Studies ◽  
Tumor Regression ◽  
Combined Therapy ◽  
Antiangiogenic Therapy ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Phase Iii ◽  
Antiangiogenic Agents

Angiogenesis is necessary for tumor growth. Drug discovery efforts have identified several potential therapeutic targets on endothelial cells and selective inhibitors capable of slowing tumor growth or producing tumor regression by blocking angiogenesis in in vivo tumor models. Certain antiangiogenic therapeutics increase the activity of cytotoxic anticancer treatments in preclinical models. More than 75 antiangiogenic compounds have entered clinical trials. Most of the early clinical testing was conducted in patients with advanced disease resistant to standard therapies. Several phase III trials have been undertaken to compare the efficacy of standard chemotherapy versus the same in combination with an experimental angiogenesis inhibitor. Preliminary results of the clinical studies suggest that single-agent antiangiogenic therapy is poorly active in advanced tumors. Although some of the results of combination trials are controversial, recent positive outcomes with an antivascular endothelial growth factor antibody combined with chemotherapy as front-line therapy of metastatic colorectal cancer have renewed enthusiasm for this therapeutic strategy. This article presents an overview of experimental and clinical studies of combined therapy with antiangiogenic agents and highlights the challenges related to the appropriate strategies for selection of the patients, study design, and choice of proper end points for preclinical and clinical studies using these agents.

scholarly journals Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states

2018 ◽  
Vol 115 (51) ◽  
pp. E11894-E11903 ◽  
Author(s):  
Eric W. Lake ◽  
Joseph M. Muretta ◽  
Andrew R. Thompson ◽  
Damien M. Rasmussen ◽  
Abir Majumdar ◽  
...  
Keyword(s):  
Large Scale ◽  
Kinase Inhibitors ◽  
Conformational Dynamics ◽  
Aurora Kinase ◽  
Activation Loop ◽  
Aurora A ◽  
Kinase Activation ◽  
Mitotic Kinase ◽  
Conformational Preferences ◽  
Wide Range

Protein kinases undergo large-scale structural changes that tightly regulate function and control recognition by small-molecule inhibitors. Methods for quantifying the conformational effects of inhibitors and linking them to an understanding of selectivity patterns have long been elusive. We have developed an ultrafast time-resolved fluorescence methodology that tracks structural movements of the kinase activation loop in solution with angstrom-level precision, and can resolve multiple structural states and quantify conformational shifts between states. Profiling a panel of clinically relevant Aurora kinase inhibitors against the mitotic kinase Aurora A revealed a wide range of conformational preferences, with all inhibitors promoting either the active DFG-in state or the inactive DFG-out state, but to widely differing extents. Remarkably, these conformational preferences explain broad patterns of inhibitor selectivity across different activation states of Aurora A, with DFG-out inhibitors preferentially binding Aurora A activated by phosphorylation on the activation loop, which dynamically samples the DFG-out state, and DFG-in inhibitors binding preferentially to Aurora A constrained in the DFG-in state by its allosteric activator Tpx2. The results suggest that many inhibitors currently in clinical development may be capable of differentiating between Aurora A signaling pathways implicated in normal mitotic control and in melanoma, neuroblastoma, and prostate cancer. The technology is applicable to a wide range of clinically important kinases and could provide a wealth of valuable structure–activity information for the development of inhibitors that exploit differences in conformational dynamics to achieve enhanced selectivity.

scholarly journals Near-infrared oxidative phosphorylation inhibitor integrates acute myeloid leukemia–targeted imaging and therapy

2021 ◽  
Vol 7 (1) ◽  
pp. eabb6104
Author(s):  
Chi Zhang ◽  
Tao Liu ◽  
Peng Luo ◽  
Li Gao ◽  
Xingyun Liao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Oxidative Phosphorylation ◽  
Myeloid Leukemia ◽  
Near Infrared ◽  
Malignant Cell ◽  
Therapeutic Effects ◽  
Disease Relapse ◽  
In Vivo Flow Cytometry ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a deadly hematological malignancy with frequent disease relapse. The biggest challenge for AML therapy is the lack of methods to target and kill the heterogeneous leukemia cells, which lead to disease relapse. Here, we describe a near-infrared (NIR) fluorescent dye, IR-26, which preferentially accumulates in the mitochondria of AML cells, depending on the hyperactive glycolysis of malignant cell, and simultaneously impairs oxidative phosphorylation (OXPHOS) to exert targeted therapeutic effects for AML cells. In particular, IR-26 also exhibits potential for real-time monitoring of AML cells with an in vivo flow cytometry (IVFC) system. Therefore, IR-26 represents a novel all-in-one agent for the integration of AML targeting, detection, and therapy, which may help to monitor disease progression and treatment responses, prevent unnecessary delays in administering upfront therapy, and improve therapeutic efficiency to the residual AML cells, which are responsible for disease relapse.

scholarly journals p53 status dictates responses of B lymphomas to monotherapy with proteasome inhibitors

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4936-4943 ◽  
Author(s):  
Duonan Yu ◽  
Martin Carroll ◽  
Andrei Thomas-Tikhonenko
Keyword(s):  
Tumor Regression ◽  
Proteasome Inhibitors ◽  
Therapeutic Effects ◽  
Wild Type ◽  
Retroviral Transduction ◽  
Myc Oncogene ◽  
Hpv E6 ◽  
P53 Status ◽  
Wild Type P53

Abstract The proapoptotic function of p53 is thought to underlie most anticancer modalities and is also activated in response to oncogenic insults, such as overexpression of the Myc oncoprotein. Here we generated tractable B lymphomas using retroviral transduction of the MYC oncogene into hematopoietic cells with 2 knock-in alleles encoding a fusion between p53 and 4-hydroxytamoxifen (4OHT) receptor (p53ERTAM). In these polyclonal tumors, Myc is the only oncogenic lesion, and p53ERTAM status can be rapidly toggled between “off” and “on” with 4OHT, provided that the Trp53 promoter has been independently activated. Although 4OHT can trigger widespread apoptosis and overt tumor regression even in the absence of DNA-damaging agents, in tumors with high levels of Mdm2 these responses are blunted. However, cotreatment with proteasome inhibitors fully restores therapeutic effects in vivo. Similarly, human Burkitt lymphomas with wild-type p53 and overexpression of Hdm2 are highly sensitive to proteasome inhibitors, unless p53 levels are reduced using the HPV-E6 ubiquitin ligase. Therefore, proteasome inhibitors could be highly effective as a monotherapy against Myc-induced lymphomas, with no need for adjuvant chemotherapy or radiation therapy. On the other hand, their efficacy is crucially dependent on the wild-type p53 status of the tumor, placing important restrictions on patient selection.

scholarly journals Desoxyepothilone B: An efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B

1998 ◽  
Vol 95 (16) ◽  
pp. 9642-9647 ◽  
Author(s):  
Ting-Chao Chou ◽  
Xiu-Guo Zhang ◽  
Aaron Balog ◽  
Dai-Shi Su ◽  
Dongfang Meng ◽  
...  
Keyword(s):  
Cell Growth ◽  
Tumor Regression ◽  
Human Tumor ◽  
Mammary Adenocarcinoma ◽  
Cross Resistance ◽  
Therapeutic Effects ◽  
Electron Microscopic ◽  
Ovarian Adenocarcinoma

A new class of 16-membered macrolides, the epothilones (Epos), has been synthesized and evaluated for antitumor potential in vitro and in vivo. Recent studies in these and other laboratories showed that epothilones and paclitaxel (paclitaxel) share similar mechanisms of action in stabilizing microtubule arrays as indicated by binding-displacement studies, substitution for paclitaxel in paclitaxel-dependent cell growth, and electron microscopic examinations. The present study examined cell growth-inhibitory effects in two rodent and three human tumor cell lines and their drug-resistant sublines. Although paclitaxel showed as much as 1,970-fold cross-resistance to the sublines resistant to paclitaxel, adriamycin, vinblastine, or actinomycin D, most epothilones exhibit little or no cross-resistance. In multidrug-resistant CCRF-CEM/VBL100 cells, IC50 values for EpoA (1), EpoB (2), desoxyEpoA (3) (dEpoA), desoxyEpoB (4) (dEpoB), and paclitaxel were 0.02, 0.002, 0.012, 0.017, and 4.14 μM, respectively. In vivo studies, using i.p. administration, indicated that the parent, EpoB, was highly toxic to mice and showed little therapeutic effect when compared with a lead compound, dEpoB. More significantly, dEpoB (25–40 mg/kg, Q2Dx5, i.p.) showed far superior therapeutic effects and lower toxicity than paclitaxel, doxorubicin, camptothecin, or vinblastine (at maximal tolerated doses) in parallel experiments. For mammary adenocarcinoma xenografts resistant to adriamycin, MCF-7/Adr, superior therapeutic effects were obtained with dEpoB compared with paclitaxel when i.p. regimens were used. For ovarian adenocarcinoma xenografts, SK-OV-3, dEpoB (i.p.), and paclitaxel (i.v.) gave similar therapeutic effects. In nude mice bearing a human mammary carcinoma xenograft (MX-1), marked tumor regression and cures were obtained with dEpoB.

Discovery of Highly Potent and Selective Pan-Aurora Kinase Inhibitors with Enhanced in Vivo Antitumor Therapeutic Index

2012 ◽  
Vol 55 (7) ◽  
pp. 3250-3260 ◽  
Author(s):  
Gang Liu ◽  
Sunny Abraham ◽  
Lan Tran ◽  
Troy D. Vickers ◽  
Shimin Xu ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Therapeutic Index ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitors

Clinical Trials in Thrombosis: Secondary Prevention of Myocardial Infarction

1976 ◽  
Vol 35 (01) ◽  
pp. 049-056 ◽  
Author(s):  
Christian R Klimt ◽  
P. H Doub ◽  
Nancy H Doub
Keyword(s):  
Myocardial Infarction ◽  
Secondary Prevention ◽  
Case Control ◽  
Therapeutic Effects ◽  
Case Control Studies ◽  
Definitive Answer ◽  
Inhibition Of Platelet Aggregation ◽  
Prospective Trials

SummaryNumerous in vivo and in vitro experiments, investigating the inhibition of platelet aggregation and the prevention of experimentally-induced thrombosis, suggest that anti-platelet drugs, such as aspirin or the combination of aspirin and dipyridamole or sulfinpyrazone, may be effective anti-thrombotic agents in man. Since 1971, seven randomized prospective trials and two case-control studies have been referenced in the literature or are currently being conducted, which evaluate the effects of aspirin, sulfinpyrazone, or dipyridamole in combination with aspirin in the secondary prevention of myocardial infarction. A critical review of these trials indicates a range of evidence from no difference to a favorable trend that antiplatelet drugs may serve as anti-thrombotic agents in man. To date, a definitive answer concerning the therapeutic effects of these drugs in the secondary prevention of coronary heart disease is not available.

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.

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