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WEE1 inhibitor

Brittany Haynes, Junko Murai, Jung-Min Lee
Poly(ADP-ribose) polymerase (PARP) inhibition serves as a potent therapeutic option eliciting synthetic lethality in cancers harboring homologous recombination (HR) repair defects, such as BRCA mutations. However, the development of resistance to PARP inhibitors (PARPis) poses a clinical challenge. Restoration of HR competency is one of the many molecular factors contributing to PARPi resistance. Combination therapy with cell cycle checkpoint (ATR, CHK1, and WEE1) inhibitors is being investigated clinically in many cancers, particularly in ovarian cancer, to enhance the efficacy and circumvent resistance to PARPis...
September 11, 2018: Cancer Treatment Reviews
Hui-Ju Hsieh, Wei Zhang, Shu-Hong Lin, Wen-Hao Yang, Jun-Zhong Wang, Jianfeng Shen, Yiran Zhang, Yiling Lu, Hua Wang, Jane Yu, Gordon B Mills, Guang Peng
Checkpoint recovery, the process that checkpoint-arrested cells with normal DNA repair capacity resume cell cycle progression, is essential for genome stability. However, the signaling network of the process has not been clearly defined. Here, we combine functional proteomics, mathematical modeling, and molecular biology to identify mTORC1, the nutrient signaling integrator, as the determinant for G2/M checkpoint recovery. Inhibition of the mTORC1 pathway delays mitotic entry after DNA damage through KDM4B-mediated regulation of CCNB1 and PLK1 transcription...
September 28, 2018: Nature Communications
Albert Job, Lisa-Maria Schmitt, Lisa von Wenserski, Brigitte Lankat-Buttgereit, Thomas M Gress, Malte Buchholz, Eike Gallmeier
The phosphoinositide 3-kinase-related kinase ATR is a central regulator of the DNA damage response. Its chemical inhibition eliminates subsets of cancer cells in various tumor types. This effect is caused at least partly by the synthetically lethal relationship between ATR and certain DNA repair genes. In a previous screen using an siRNA library against DNA repair genes, we identified PRIM1, a part of the polymerase α-primase complex, as acting synthetically lethal with ATR. Applying a genetic ATR knock-in model of colorectal cancer cells, we confirmed that PRIM1 depletion inhibited proliferation of ATR-deficient cells and excluded artifacts due to clonal variation using an ATR reexpressing cell clone...
September 23, 2018: Neoplasia: An International Journal for Oncology Research
Yanchao Duan, Xin Dong, Jing Nie, Peng Li, Fei Lu, Daoxin Ma, Chunyan Ji
Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy affecting pediatric and adult populations. Although the outcomes of ALL in children have improved markedly in previous years, limited treatment strategies are available at present for adult patients with ALL. Wee1 is a crucial cell cycle checkpoint kinase of G2/M that regulates cell cycle progression and maintains chromatin integrity. MK-1775, a selective inhibitor of Wee1 has recently been identified to be able to induce apoptosis of tumor cells by abrogating G2/M checkpoint...
October 2018: Oncology Letters
Radoslaw Szmyd, Joanna Niska-Blakie, M Kasim Diril, Patrícia Renck Nunes, Konstantinos Tzelepis, Aurélie Lacroix, Noémi van Hul, Lih-Wen Deng, Joao Matos, Oliver Dreesen, Xavier Bisteau, Philipp Kaldis
Cell cycle regulation, especially faithful DNA replication and mitosis, are crucial to maintain genome stability. Cyclin-dependent kinase (CDK)/cyclin complexes drive most processes in cellular proliferation. In response to DNA damage, cell cycle surveillance mechanisms enable normal cells to arrest and undergo repair processes. Perturbations in genomic stability can lead to tumor development and suggest that cell cycle regulators could be effective targets in anticancer therapy. However, many clinical trials ended in failure due to off-target effects of the inhibitors used...
September 6, 2018: Oncogene
Yaping Li, Yinglan Pu, Hui Liu, Li Zhang, Xingyong Liu, Yan Li, Zhili Zuo
Wee1 plays a critical role in the arrest of G2/M cell cycle for DNA repair before entering mitosis. Many cancer cells have been identified as overexpression of Wee1. In this research, pharmacophore modeling, molecular docking and molecular dynamics simulation approaches were constructed to identify novel potential Wee1 inhibitors. A compound 8 was found to have a novel skeleton against Wee1 with an IC50 value of 22.32 µM and a Ki value of 13.11 µM. Kinetic assays were employed to evaluate the compound 8 as a competitive inhibitor...
September 2018: Journal of Computer-aided Molecular Design
Xian Chen, Kwang Hui Low, Angela Alexander, Yufeng Jiang, Cansu Karakas, Kenneth R Hess, Jason P Carey, Tuyen Bui, Smruthi Vijayaraghavan, Kurt W Evans, Min Yi, D Christian Ellis, Kwok-Leung Cheung, Ian O Ellis, Siqing Fu, Funda Meric-Bernstam, Kelly K Hunt, Khandan Keyomarsi
PURPOSE: Poor prognosis in triple-negative breast cancer (TNBC) is due to an aggressive phenotype and lack of biomarker-driven targeted therapies. Overexpression of cyclin E and phosphorylated-CDK2 are correlated with poor survival in TNBC patients, and the absence of CDK2 desensitizes cells to inhibition of Wee1 kinase, a key cell cycle regulator. We hypothesize that cyclin E expression can predict response to therapies, which include the Wee1 kinase inhibitor, AZD1775. EXPERIMENTAL DESIGN: Mono and combination therapies with AZD1775 were evaluated in TNBC cell lines and multiple patient derived xenograft (PDX) models with different cyclin E expression profiles...
September 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Bin Fang, Aarthi Kannan, Tao Guo, Ling Gao
Purpose: Small cell lung cancer (SCLC) is highly lethal with no effective therapy. Wee1 kinase inhibitor AZD1775 (MK-1775) and mTOR kinase inhibitor MLN0128 (TAK228) are in clinical trials for relapsed SCLC and recurrent lung cancer, respectively. However, there is no preclinical data combining these two drugs in human cancers. Methods: In this study, we set to investigate the combinatorial anti-tumor effects of AZD1775 and MLN0128 on two human SCLC cell lines H69 and H82 in vitro and in vivo. Results: We have found that AZD1775 or MLN0128 treatment results in remarkably suppressed cell proliferation and increased cell death in vitro, what's more, the salient finding here is the potent anti-tumor effect observed in combinatorial treatment in H82 xenograft tumor...
2018: International Journal of Biological Sciences
Siqing Fu, Yudong Wang, Khandan Keyomarsi, Funda Meric-Bernstein
Wee1 kinase controls the G2-M checkpoint. Wee1 inhibition by AZD1775 allows cells with a deregulated G1 checkpoint to progress, resulting in catastrophe and apoptosis. The challenges ahead are in the establishment of the optimum dosing schedule either alone or in combination and the identification of patients with specific biomarker profiles who benefit most. Areas covered: This article provides an overview of AZD1775, based on English peer-reviewed articles on MEDLINE. The authors highlight the data from the published preclinical and clinical studies...
September 2018: Expert Opinion on Investigational Drugs
Subhayan Sur, Reina Sasaki, Pradip Devhare, Robert Steele, Ranjit Ray, Ratna B Ray
Chronic hepatitis C virus (HCV) infection may lead to end-stage liver disease, including hepatocellular carcinoma (HCC). We have shown previously that microRNA-373 (miR-373) is upregulated in HCV-infected human liver biopsy specimens. To gain insight into the role of miR-373 in HCV-mediated pathogenesis, we investigated its interacting partner for hepatocyte growth regulation. Transcriptome sequencing (RNA-seq) data revealed that Wee1 is associated with miR-373 and is a direct target. Interestingly, higher expression of Wee1 was noted in HCV-infected hepatocytes than in uninfected hepatocytes, suggesting that other factors may block miR-373-mediated Wee1 inhibition...
October 15, 2018: Journal of Virology
Yanqiu Hu, Lu Zhou, Xiaohong Zhu, Duoqian Dai, Yinfeng Bao, Yaping Qiu
Wee1-like protein kinase (Wee1) is a tyrosine kinase that regulates the G2 checkpoint and prevents entry into mitosis in response to DNA damage. Based on a series of signaling pathways initiated by Wee1, Wee1 has been recognized as a potential target for cancer therapy. In order to discover potent Wee1 inhibitors with novel scaffolds, ligand-based pharmacophore model has been built based on 101 known Wee1 inhibitors. Then the best pharmacophore model, AADRRR.340, with good PLS statistics (R2 = 0.9212, Q2 = 0...
July 27, 2018: Journal of Biomolecular Structure & Dynamics
Dongshao Chen, Xiaoting Lin, Jing Gao, Lin Shen, Zhongwu Li, Bin Dong, Cheng Zhang, Xiaotian Zhang
Based on the mechanisms by which Wee1 inhibitor and cisplatin played their own role, a promising strategy of Wee1 inhibitor combined with cisplatin was proposed, which was investigated in gastric cancer (GC). Either Wee1 inhibitor AZD1775 or cisplatin alone had a certain inhibitory effect on in vitro cell proliferation; however, the inhibitory effect was more significant when AZD1775 combined with cisplatin in vitro and in vivo . The underlying mechanisms unveiled that the increased DNA damage indicated by increased γ H2AX protein, as well as augmented cell apoptosis indicated by upregulated proapoptotic proteins, was responsible for the significant inhibitory effect of AZD1775 plus cisplatin...
2018: BioMed Research International
Xiaoting Lin, Dongshao Chen, Cheng Zhang, Xiaotian Zhang, Zhongwu Li, Bin Dong, Jing Gao, Lin Shen
BACKGROUND: Targeting poly ADP-ribose polymerase (PARP) has been recently identified as a promising option against gastric cancer (GC). However, PARP inhibitors alone achieve limited efficacy. Combination strategies, especially with homologous recombination (HR) impairment, are of great hope to optimize PARP inhibitor's efficacy and expand target populations but remains largely unknown. Herein, we investigated whether a WEE1/ Polo-like kinase 1 (PLK1) dual inhibitor AZD1775 reported to impair HR augmented anticancer activity of a PARP inhibitor olaparib and its underlying mechanisms...
June 28, 2018: Journal of Experimental & Clinical Cancer Research: CR
Alice Lallo, Kristopher K Frese, Christopher J Morrow, Robert Sloane, Sakshi Gulati, Maximillian W Schenk, Francesca Trapani, Nicole Simms, Melanie Galvin, Stewart Brown, Cassandra L Hodgkinson, Lynsey Priest, Adina Hughes, Zhongwu Lai, Elaine Cadogan, Garima Khandelwal, Kathryn L Simpson, Crispin Miller, Fiona Blackhall, Mark J O'Connor, Caroline Dive
Purpose: Introduced in 1987, platinum-based chemotherapy remains standard of care for small cell lung cancer (SCLC), a most aggressive, recalcitrant tumor. Prominent barriers to progress are paucity of tumor tissue to identify drug targets and patient-relevant models to interrogate novel therapies. Following our development of circulating tumor cell patient-derived explants (CDX) as models that faithfully mirror patient disease, here we exploit CDX to examine new therapeutic options for SCLC. Experimental Design: We investigated the efficacy of the PARP inhibitor olaparib alone or in combination with the WEE1 kinase inhibitor AZD1775 in 10 phenotypically distinct SCLC CDX in vivo and/or ex vivo These CDX represent chemosensitive and chemorefractory disease including the first reported paired CDX generated longitudinally before treatment and upon disease progression...
June 25, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Yusuke Oku, Naoyuki Nishiya, Takaaki Tazawa, Takaya Kobayashi, Nanami Umezawa, Yasuyo Sugawara, Yoshimasa Uehara
The main reasons for failure of cancer chemotherapy are intrinsic and acquired drug resistance. The Hippo pathway effector Yes-associated protein (YAP) is associated with resistance to both cytotoxic and molecular targeted drugs. Several lines of evidence indicate that YAP activates transcriptional programmes to promote cell cycle progression and DNA damage responses. Therefore, we hypothesised that YAP is involved in the sensitivity of cancer cells to small-molecule agents targeting cell cycle-related proteins...
June 2018: FEBS Open Bio
Jay Friedman, Megan Morisada, Lillian Sun, Ellen C Moore, Michelle Padget, James W Hodge, Jeffrey Schlom, Sofia R Gameiro, Clint T Allen
BACKGROUND: Natural killer (NK) cells recognize and lyse target tumor cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor cell resistance to granzyme B and how this alters NK cell killing is not clearly defined. METHODS: Tumor cell sensitivity to cultured murine KIL and human high affinity NK (haNK) cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis...
June 21, 2018: Journal for Immunotherapy of Cancer
Leslie A Parsels, Joshua D Parsels, Daria M Tanska, Jonathan Maybaum, Theodore S Lawrence, Meredith A Morgan
Small molecule inhibitors of the checkpoint proteins CHK1 and WEE1 are currently in clinical development in combination with the antimetabolite gemcitabine. It is unclear, however, if there is a therapeutic advantage to CHK1 vs. WEE1 inhibition for chemosensitization. The goals of this study were to directly compare the relative efficacies of the CHK1 inhibitor MK8776 and the WEE1 inhibitor AZD1775 to sensitize pancreatic cancer cell lines to gemcitabine and to identify pharmacodynamic biomarkers predictive of chemosensitization...
2018: Cell Cycle
Christopher J Matheson, Kimberly A Casalvieri, Donald S Backos, Philip Reigan
WEE1 kinase regulates the G2 /M cell-cycle checkpoint, a critical mechanism for DNA repair in cancer cells that can confer resistance to DNA-damaging agents. We previously reported a series of pyrazolopyrimidinones based on AZD1775, a known WEE1 inhibitor, as an initial investigation into the structural requirements for WEE1 inhibition. Our lead inhibitor demonstrated WEE1 inhibition in the same nanomolar range as AZD1775, and potentiated the effects of cisplatin in medulloblastoma cells, but had reduced single-agent cytotoxicity...
August 20, 2018: ChemMedChem
Nader Sanai, Jing Li, Julie Boerner, Karri Stark, Jianmei Wu, Seongho Kim, Alanna Derogatis, Shwetal Mehta, Harshil D Dhruv, Lance K Heilbrun, Michael E Berens, Patricia M LoRusso
Purpose: AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood-brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma. Patients and Methods: Twenty adult patients received a single dose of AZD1775 prior to tumor resection and enrolled in either a dose-escalation arm or a time-escalation arm...
August 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Xiangbing Meng, Jianling Bi, Yujun Li, Shujie Yang, Yuping Zhang, Mary Li, Haitao Liu, Yiyang Li, Megan E Mcdonald, Kristina W Thiel, Kuo-Kuang Wen, Xinhao Wang, Meng Wu, Kimberly K Leslie
Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function...
May 19, 2018: Cancers
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