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WEE1 inhibitor

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...
August 13, 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 previously shown that microRNA-373 (miR-373) is upregulated in HCV infected human liver biopsy specimens. To gain insights the role of miR-373 in HCV mediated pathogenesis, we investigated its interacting partner for hepatocyte growth regulation. 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, suggesting other factors may block miR-373 mediated Wee1 inhibition...
August 8, 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 Morrow, Robert Szczepaniak Sloane, Sakshi Gulati, Maximilian W Schenk, Francesca Trapani, Nicole Simms, Melanie Galvin, Stewart Brown, Cassandra L Hodgkinson, Lynsey Priest, Adina M Hughes, Zhongwu Lai, Elaine B Cadogan, Garima Khandelwal, Kathryn L Simpson, Crispin Miller, Fiona H Blackhall, Mark J O'Connor, Caroline Dive
PURPOSE: Introduced in 1987, platinum-based chemotherapy remains standard of care for small cell lung cancer, 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 tumour cell patient-derived explants (CDX) as models that faithfully mirror patient disease, here we exploit CDX to examine new therapeutic options for small cell lung cancer...
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...
July 18, 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...
June 8, 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. Experimental Design: 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...
May 24, 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
Duane H Hamilton, Kristen K McCampbell, Claudia Palena
The acquisition of mesenchymal features by carcinoma cells is now recognized as a driver of metastasis and tumor resistance to a range of anticancer therapeutics, including chemotherapy, radiation, and certain small-molecule targeted therapies. With the recent successful implementation of immunotherapies for the treatment of various types of cancer, there is growing interest in understanding whether an immunological approach could be effective at eradicating carcinoma cells bearing mesenchymal features. Recent studies, however, demonstrated that carcinoma cells that have acquired mesenchymal features may also exhibit decreased susceptibility to lysis mediated by immune effector cells, including antigen-specific CD8+ T cells, innate natural killer (NK), and lymphokine-activated killer (LAK) cells...
2018: Frontiers in Oncology
Siang-Boon Koh, Yann Wallez, Charles R Dunlop, Sandra Bernaldo de Quirós Fernández, Tashinga E Bapiro, Frances M Richards, Duncan I Jodrell
Combination of cytotoxic therapy with emerging DNA damage response inhibitors (DDRi) has been limited by tolerability issues. However, the goal of most combination trials has been to administer DDRi with standard-of-care doses of chemotherapy. We hypothesized that mechanism-guided treatment scheduling could reduce the incidence of dose-limiting toxicities and enable tolerable multitherapeutic regimens. Integrative analyses of mathematical modeling and single-cell assays distinguished the synergy kinetics of WEE1 inhibitor (WEE1i) from CHEK1 inhibitor (CHK1i) by potency, spatiotemporal perturbation, and mitotic effects when combined with gemcitabine...
June 1, 2018: Cancer Research
Jeff C Liu, Letizia Granieri, Mariusz Shrestha, Dong-Yu Wang, Ioulia Vorobieva, Elizabeth A Rubie, Rob Jones, YoungJun Ju, Giovanna Pellecchia, Zhe Jiang, Carlo A Palmerini, Yaacov Ben-David, Sean E Egan, James R Woodgett, Gary D Bader, Alessandro Datti, Eldad Zacksenhaus
CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition...
April 3, 2018: Cell Reports
Juan Jin, Hehui Fang, Fang Yang, Wenfei Ji, Nan Guan, Zijia Sun, Yaqin Shi, Guohua Zhou, Xiaoxiang Guan
Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that poses a clinical challenge. Thus, new therapy strategies are urgently needed. The selective WEE1 inhibitor, AZD1775, has shown strong anti-proliferative effects on a variety of tumors. Here, we first demonstrate that inhibition of ATR by selective inhibitor AZD6738 can enhance AZD1775-caused growth inhibition in TNBC. Our results show that the enhanced cell death is attributed to repressed DNA damage repair and excessive replication stress, thereby causing increased DNA damage reflected by accumulation of the DNA double-strand-break marker γH2AX...
May 2018: Neoplasia: An International Journal for Oncology Research
Josep V Forment, Mark J O'Connor
Many conventional chemotherapies used in cancer treatment exert their effect by inflicting DNA damage. Highly proliferative tissues, as well as tumour cells, are particularly vulnerable to this damage resulting in unwanted toxicities. In contrast, a targeted therapeutic approach has the aim of specifically eliminating cancer cells but with a reduced effect on healthy tissue. New therapies have been developed that target the replication stress response (RSR), a branch of the broader DNA damage response that specifically deals with interferences of the normal DNA replication program...
March 24, 2018: Pharmacology & Therapeutics
Eduardo Méndez, Cristina P Rodriguez, Michael C Kao, Sharat Raju, Ahmed Diab, R Alex Harbison, Eric Q Konnick, Ganesh M Mugundu, Rafael Santana-Davila, Renato Martins, Neal D Futran, Laura Q M Chow
Purpose: The WEE1 tyrosine kinase regulates G2 -M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel. Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation...
June 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Sirimanas Jiaranuchart, Atsushi Kaida, Yusuke Onozato, Hiroyuki Harada, Masahiko Miura
OBJECTIVE: The objective of this study was to characterize the DNA damage response in two human oral cancer cell lines following X-irradiation. DESIGN: To visualize radiation-induced cell cycle alterations, two human oral cancer cell lines, HSC3 and HSC4, expressing fluorescent ubiquitination-based cell cycle indicator (Fucci) were established in this study. G2 arrest kinetics following irradiation were obtained from two-color flow cytometric analysis and pedigrees of Fucci fluorescence...
June 2018: Archives of Oral Biology
Corey A H Allard, Hannah E Opalko, Ko-Wei Liu, Uche Medoh, James B Moseley
Cell size control requires mechanisms that link cell growth with Cdk1 activity. In fission yeast, the protein kinase Cdr2 forms cortical nodes that include the Cdk1 inhibitor Wee1 along with the Wee1-inhibitory kinase Cdr1. We investigated how nodes inhibit Wee1 during cell growth. Biochemical fractionation revealed that Cdr2 nodes were megadalton structures enriched for activated Cdr2, which increases in level during interphase growth. In live-cell total internal reflection fluorescence microscopy videos, Cdr2 and Cdr1 remained constant at nodes over time, but Wee1 localized to nodes in short bursts...
May 7, 2018: Journal of Cell Biology
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