Dual inhibition of WEE1 and CHK1 seems to be an interesting option, but PD0407824 has only been tested in ovarian cancer cells as a CHK1 inhibitor, where it led to sensitization to cisplatin . Ovarian cancer is the sixth leading cause of cancer mortality among women in developed countries. Among Shares of Zentalis Pharmaceuticals (ZNTL) dropped 30% on Friday after releasing initial phase 1b efficacy data on its candidate, ZN-c3, in ovarian cancer patients. In this review, we summarize recent advances with Wee1 inhibitors, statins, and mevalonate pathway inhibitors in cancers with p53 mutations. Wee1 is emerging as a potentially important therapeutic target for a range of solid tumors, including ovarian and uterine cancer. MedPage Today (1/25, Ingram) reports researchers found in a phase 2 trial that the addition of the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and (2021) European Society for Medical Oncology Zentalis Pharma Posts Initial Clinical Data On Its Wee1 Inhibitor In Ovarian Cancer. Wee1 Inhibition in Recurrent Serous Uterine Cancer: Science Paving the Way in a Challenging Disease Ainhoa Madariaga, MD1,2and Amit M. Oza, MD1,2 The incidence of endometrial In this study, we characterised the widely used high grade serous ovarian cancer (HGSOC) cell line NIH-OVCAR3 using bioinformatics, cytotoxicity assays and molecular/functional analyses of DNA damage response (DDR) These platinum-sensitive ovarian cancer AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. Vaccines; e.g.,DPX-Survivac . Cancer Cell (2019). Cancer cells, due to mutations in the p53/pRb pathway, frequently exhibit a deficient G1-arrest and mostly depend on G2-arrest [].WEE1 inhibitors appear to have potential high efficiency in p53-deficient ovarian cancers, generating a condition of synthetic lethality among p53 mutant tumors. Here, we report that the inactivation of YAP sensitises the OVCAR-8 ovarian cancer cell line to AZD1775, a small-molecule WEE1 kinase inhibitor. Hirai H, Arai T, Okada M, et al. MK-1775, a small molecule Wee1 inhibitor, enhances antitumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biol Ther. 2010;9 (7):51422. Maier P, Hartmann L, Wenz F, Herskind C. Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization. Given the biological significance of in vitro data, we next investigated the antitumor activity induced by AZD1775 and AZD6738 in vivo. Vaccines; e.g.,DPX-Survivac . Cancer cells, due to mutations in the p53/pRb pathway, frequently exhibit a deficient G1-arrest and mostly depend on G2-arrest [ 24 ]. WEE1 inhibitors appear to have potential high efficiency in p53-deficient ovarian cancers, generating a condition of synthetic lethality among p53 mutant tumors. The present study aimed at examining the in vitro and in vivo antitumor activity of MK1775, a potent pharmacological inhibitor of WEE1, as a single agent against ovarian cancer cells. Zentalis Pharmaceuticals Announces Positive Initial Clinical Data on ZN-c3, its Wee1 Inhibitor, in Patients with Advanced Ovarian Cancer at AACR ZN-c3 in combination with | June 27, 2022 We are focused on the creation of differentiated small molecule treatments targeting fundamental biological pathways of cancer. MK-1775 is an investigational orally available inhibitor of the cell cycle Phase 1b dose-escalation study of ZN-c3, a Wee1 inhibitor, in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian, peritoneal, or fallopian tube cancer Fu, S. et al. WEE1 inhibitors are well tolerated with fewer adverse reactions. Cancer cells, due to mutations in the p53/pRb pathway, frequently exhibit a deficient G1-arrest and mostly depend on G2-arrest [].WEE1 inhibitors appear to have potential Wee1 inhibition remains a promising therapeutic approach to treating an array of solid tumors, including advanced ovarian cancer, and these results further support the class

What is the best chemotherapy for ovarian cancer? Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer Expert Views on The Future of PARP Inhibitors in Ovarian Cancer. Adding the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and death in women with recurrent, platinum-resistant or -refractory ovarian cancer, a randomized phase II trial showed. WEE1 is a key regulator of the cell cycle that has been a target of cancer drug discovery efforts for more than a decade. We considered an increase in genomic instability induced by WEE1 inhibition might be used to augment the effects of drugs targeting DNA repair protein. WEE1 kinase plays a crucial role in the G2M cell-cycle checkpoint arrest for DNA repair before mitotic entry. These include inhibitors of signaling through the phosphatidylinositol 3-kinase (PI3K) pathway, vascular endothelial growth factor receptor (VEGFR), and cell cycle checkpoints including WEE1 [, , ]. Combination treatment of cancer cells with ATR and Wee1 inhibitors leads to centromere fragmentation and mitotic catastrophe. In a phase I study, the The study results were recently presented and suggested the efficacy of adavosertib alone and combined with olaparib. AZD1775 is a Wee1 inhibitor that has been combined with carboplatin and paclitaxel in the platinum-sensitive recurrent setting of ovarian cancer. Combinations of PARP inhibitors with other anticancer therapies in ovarian cancer; PARP plus novel Wee1 inhibitors; Final Thoughts and Takeaways. Wee1. In accordance with our results, pharmacologic inhibition of G2 checkpoint kinases Wee1 and Chk1 has been shown to have anti-tumoral effects in neuroblastoma cells both in vitro and in vivo 21 and cause DNA double-strand breaks in cancer cells in the absence of DNA-damaging chemotherapeutic drugs. The cytotoxicity of MK1775 was examined in a Adding the WEE1 inhibitor AZD1775 to carboplatin offered The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian WEE1 inhibitor promotes cancer cells to prematurely enter mitosis as a result of bypassing the G2 cell-cycle checkpoint [6]aswellasdelaysmitoticexit,resultinginmitoticarrest[7]. The cytotoxicity of MK1775 was examined in a panel of tumor cells using MTT in vitro.

The Wee1 (WEE1hu) inhibitor adavosertib and gemcitabine have shown preclinical synergy and promising activity in early phase clinical trials. We aimed to determine the efficacy of this combination in patients with ovarian cancer. New results involving the Wee1 inhibitor adavosertib brought improved survival benefits in a hard-to-treat type of ovarian cancer, but trials in the pipeline suggest the positive Schrdinger is on track to select a Wee1 development candidate later this year. Inhibition of Wee1 sensitizes cancer cells to antimetabolite chemotherapeutics in vitro and in vivo, independent of p53 functionality. Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas. ].

The study results were recently presented and suggested the efficacy of adavosertib alone and combined with olaparib. Objective: As a result of TP53 gene mutation high grade serous ovarian cancer (HGSOC) is dependent on the G2 checkpoint for the repair of DNA damage and survival. [34] verified through animal experiments that Wee1 inhibitor MK1775 as a single preparation has an inhibitory effect on tumor cells of ovarian cancer, and Wee1 may

Using our industry expertise, we have developed an integrated approach to identify and overcome the limitations of current cancer therapeutics, enabling us to design better small molecules for improved patient outcomes. In ovarian cancer, melanoma, and glioma tumors, high expression of Wee1 is associated with poor outcome.

At the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, CancerNetwork spoke with Shannon N. Westin, MD, MPH, of the University of Texas MD Cyclin E (CCNE1) is overexpressed in 25% of high grade serous ovarian cancers Pre-clinical studies showed that treatment with adavosertib inhibits the growth of ovarian cancer cells in vitro and in vivo.

More than 40% BRCA1/2 CHICAGO AstraZeneca's investigational WEE1 inhibitor adavosertib showed potential in biomarker-selected advanced ovarian cancer populations in two studies presented Zhiyuan Dou 1,2, Chunping Qiu 1, HJURP was a less-potent WEE1 inhibitor than PD0166285, but was more selective for WEE1 (IC 50 = 97 nM) and CHK1 (IC only been tested in ovarian cancer cells as a CHK1 inhibitor, where it led to PD0166285 has been used to examine the effect of WEE1 inhibition in cervical cancer, colon cancer, lung cancer, melanoma, ovarian cancer, and hepatocellular carcinoma Zhang et al. The observed clinical efficacy of a Wee1 inhibitor combined with gemcitabine supports ongoing assessment of DNA damage response drugs in high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress. The potent WEE1 inhibitor AZD1775 has advanced to clinical trials in combination with DNA-damaging therapies in various cancer types.

Normal cells repair damaged DNA during G1 arrest; however, cancer cells often It has been proposed that WEE1 inhibitor Others in this space include Debiopharm, although the French firm appears to have cooled on the mechanism. Wee1-like protein kinase (WEE1) contributes to the upstream regulation of the cyclin-dependent kinase High-grade serous ovarian cancer (HGSOC) is characterized by universal p53 mutation, the more common gain of function or a LOF null mutation, the WEE1 inhibitor Program Director. 3.2 WEE1 and ATR inhibition significantly delayed tumor growth in immune-competent mouse models of ovarian cancer. The present study aimed at examining the in vitro ZN-c3 was generally well-tolerated in combination with chemotherapy and exhibited lower hematologic toxicity and a better gastrointestinal tolerability profile than the Wee1 inhibitor class. The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed.

At present, several PAPRi targeting poly (ADP-ribose) polymerase (PARP) have been approved for ovarian cancer and breast cancer indications.

Four weeks into treatment, it saw a large rapid drop in blood levels of CA-125, an antigen used to monitor certain cancers. Zentaliss earlier work also includes an ovarian cancer trial testing its Wee1 agent in combination with Glaxosmithklines Zejula, a Parp inhibitor that also works by damaging DNA repair pathways. indicate that disruption of WEE1 may enhance the cell killing effects of some anticancer agents. Increased expression of WEE1 has been associated with the poor prognosis of patients with ovarian cancer. Chief, Division of Gynecologic Oncology The combination of Wee1 inhibitor C3 (ZnC3) with paclitaxel chemotherapy has Typically, PARP A total of 2 x 106 OVCAR8 ovarian cancer cells were injected subcutaneously (s.c.) and AZD1775 activates the PERK and IRE1 branches of UPR in ovarian cancer cells exclusively with mtTP53. This randomized phase II clinical trial studies how well gemcitabine hydrochloride and WEE1 inhibitor MK-1775 work compared to gemcitabine hydrochloride alone in treating What was the rationale behind adding a Wee1 inhibitor in the EFFORT?

Being the pivotal negative regulator of Cdk1/Cyclin B1 activity, Wee1 kinase is required for normal entry into and exit from mitosis. Zentalis Pharma Posts Initial Clinical Data On Its Wee1 Inhibitor In Ovarian Cancer. Importantly, WEE1 inhibitors are also antimitotic inhibitors by inducing mitotic arrest resulting in cell death regardless of cell-cycle phase prior to treatment. The combination of chemotherapy with The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. However, PARPi resistance is ubiquitous in clinic. Several reproductive cell death modes can lead to the inability of a cell to reproduce after exposure to genotoxic stress (31, 32). In a phase I study, the In cancer cells recurring after chemotherapy for medulloblastoma, vulvar squamous cell carcinoma, and malignant ovarian cancer, a single WEE1 inhibitor, AZD1775, can inhibit tumors.

Zentalis Pharmaceuticals is developing a WEE1 inhibitor that it hopes to combine with PARP inhibitors and other cancer medicines to boost their efficacyand its early phase 1 data are promising. First, we established an ovarian cancer model in C57BL/6 mice using ID8 cells. WEE1 Inhibitors Show Strong Preclinical Activity and Clinical Responses 6 (1) Fang, Y. In vitro studies showed that simultaneous Ursula Matulonis, MD.

MedPage Today (1/25, Ingram) reports researchers found in a phase 2 trial that the addition of the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and death in women with recurrent, platinum-resistant or -refractory ovarian cancer.The trials results were published in The Lancet.

MK-1775 has a high affinity for WEE1 and is the preferred WEE1 inhibitor. Adding the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and death in women with recurrent, platinum-resistant or -refractory ovarian First, ovarian cancer cells, transfected with HPV16 E6 gene to degrade p53, were more sensitive to irradiation in combination with the WEE1 inhibitor PD0166285 than p53 wild Here, we show the synergy of BET bromodomain inhibition with PARP inhibition in BRCA -proficient ovarian cancers due to mitotic catastrophe. Antibody-drug conjugates (ADC); e.g,Mirvetuximab soravtansine,for which new clinical trial results were published in May 2020 ; Targeted therapies; e.g.,the ATR inhibitor AZD6738,the Wee1 inhibitor adavosertib,and the anti-DLL4/VEGF bispecific antibody navicixizumab The cancer cells become very dependent on the checkpoint that is regulated by Wee1. MK-1775 is an investigational orally available inhibitor of the cell cycle checkpoint protein WEE1. The protein WEE1 may help to repair the damaged tumor cells, so the tumor continues to grow. Adding the Wee1 inhibitor adavosertib to gemcitabine reduced the risk of disease progression and death in women with recurrent, platinum-resistant or -refractory ovarian Our aim was to characterise resistance mechanisms to WEE1 inhibitor AZD1775 and identify ways to overcome resistance ready for use in the clinic. ovarian cancer. In order to be effective models to identify biomarkers of chemotherapy response, cancer cell lines require thorough characterization.

Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitorspersist suggesting that sequential administration of PARP and WEE1 inhibitors Impact: Further study of adavosertib in this cancer and biomarkers of WEE1 inhibition response is warranted. A fourth to a fifth of unselected EOC patients carry pathogenic variants (PVs) in a number of genes, the majority of which encode for proteins involved in DNA mismatch repair (MMR) pathways.

A single dose of Wee1 inhibitor C3 can improve quality of life for women with stage IV ovarian cancer. The present study aimed at examining the in vitro and in vivo antitumor activity of MK1775, a potent pharmacological inhibitor of WEE1, as a single agent against ovarian cancer cells. Treatment of BRCA-proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. PARP inhibitors such as Merck and AstraZenecas Lynparza have changed the game for patients with ovarian cancer, but theyre still not a cure, as cancers can outsmart The WEE1 inhibitor, adavosertib, was studied as a single-agent or combined with olaparib in women with PARP-inhibitor resistant ovarian cancer in the phase II non-comparative EFFORT trial.

Following a median of three prior lines of therapy, women with platinum-resistant or platinum-refractory high-grade serous ovarian cancer received gemcitabine plus either the Wee1-like protein kinase (WEE1) physiologically serves a key function in maintaining the integrity of the cell genome through mediating the activation of cyclin-dependent kinase (CDK)1 and CDK2.

Moreover, synergistic activity was also seen for PARP and MEK inhibitor combinations in RAS mutant tumors . Inhibition of Wee1 allows for accumulation of DNA damage, triggering DNA breakage and apoptosis in tumor cells. HJURP Promotes Malignant Progression and Mediates Sensitivity to Cisplatin and WEE1-inhibitor in Serous Ovarian Cancer . Inhibition of wee1 either by the pyrido-pyrimidine derivative (PD0166285) or via siRNA gene knockdown has been shown to sensitize ovarian, colon, cervical, osteosarcoma, Dave Levitan. Figure 1.

MK-1775 is being evaluated in Phase IIa clinical trials for the treatment of patients with P53-deficient ovarian cancer. Restriction of the G2/M checkpoint by WEE1 inhibitor AZD1775 results in disturbed proteostasis and UPR activation in ovarian cancer cells with TP53 mutations, which Preclinical data indicate that disruption of WEE1 may enhance the cell killing effects of some anticancer agents. One of the mechanisms of resistance to PARP inhibition can occur through the cell cycle and essentially in tumors that have P53 mutations, which is arguably almost every high-grade ovarian cancer. Purpose AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. November 2, 2016. WEE1 inhibitor MK-1775 may block the WEE1 protein activity and may increase the The WEE1 inhibitor, adavosertib, was studied as a single-agent or combined with olaparib in women with PARP-inhibitor resistant ovarian cancer in the phase II non-comparative EFFORT trial. WEE1 inhibitor promotes cancer cells to prematurely enter mitosis as a result of bypassing the G2 cell-cycle checkpoint [6]aswellasdelaysmitoticexit,resultinginmitoticarrest[7]. The ovarian cancer patient saw targeted tumors shrink by about 56%. Treatment of BRCA -proficient ovarian cancer cells with the BET inhibitor JQ1 downregulated the G2-M cell-cycle checkpoint regulator WEE1 and the DNA-damage response factor TOPBP1. ZN-c3 was generally well-tolerated in combination with chemotherapy and exhibited lower hematologic toxicity and a better gastrointestinal tolerability profile than the Faculty. About Merck Importantly, WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability. "Identifying and overcoming a mechanism of resistance to WEE1 kinase inhibitor AZD1775 in high grade serous ovarian cancer cells." Antibody-drug conjugates (ADC); e.g,Mirvetuximab soravtansine,for which new clinical trial results were published in May 2020 ; Targeted therapies; e.g.,the ATR inhibitor AZD6738,the Wee1 inhibitor adavosertib,and the anti-DLL4/VEGF bispecific antibody navicixizumab The lead novel candidate, the WEE1 inhibitor Therefore, we hypothesised that YAP is involved in the sensitivity of cancer cells to small-molecule agents targeting cell cycle-related proteins. Epithelial ovarian cancer (EOC) is one of the cancers most influenced by hereditary factors. Restriction of the G2/M checkpoint by WEE1 inhibitor AZD1775 results in disturbed proteostasis and UPR activation in ovarian cancer cells with TP53 mutations, which is mediated by the NF-B-governed SASP. What is the best chemotherapy for ovarian cancer?

This early phase I trial tests the safety and side effects of ZN-c3 in treating patients with triple-negative breast cancer or ovarian cancer that have spread to other parts of CHICAGO AstraZenecas investigational WEE1 inhibitor adavosertib showed potential in biomarker-selected advanced ovarian cancer populations in two studies presented Due to the DNA repair defect, BRCA1/2 deficient tumor cells are more sensitive to PARP inhibitors (PARPi) through the mechanism of synthetic lethality. Zentalis Pharmaceuticals Inc ZNTL announced initial efficacy and safety data from the Novel WEE1 Inhibitor Increases Chemotherapy Efficacy in Ovarian Cancer. Uterine serous carcinoma (USC), an aggressive form of Patients with Advanced Ovarian Cancer at AACR April 8, 2022 profile in comparison to the Wee1 inhibitor class. The PVs in BRCA1 and BRCA2 genes are responsible for a substantial fraction of hereditary EOC.