WEE1 inhibitor

Breast cancer is the most prevalent malignancy among women worldwide. Despite significant advances in treatment, it remains one of the leading causes of female mortality. The inability to effectively treat advanced and/or treatment-resistant breast cancer demonstrates the need to develop novel treatment strategies and targeted therapies. Centrosomes and their associated proteins have been shown to play key roles in the pathogenesis of breast cancer and thus represent promising targets for drug and biomarker development...

Despite the recent advancement in diagnosis and therapy, pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is still the most lethal cancer with a low five-year survival rate. There is an urgent need to develop new therapies to address this issue. In this study, we developed a treatment strategy by modifying tumor suppressor miRNAs, miR-15a and miR-194, with the chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics, Gem-miR-15a and Gem-miR-194, respectively. In a panel of PDAC cell lines, we found that Gem-miR-15a and Gem-miR-194 induce cell-cycle arrest and apoptosis, and these mimics are potent inhibitors with IC50 values up to several hundred fold less than their native counterparts or Gem alone...

BACKGROUND: One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. METHODS: RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients...

Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal-organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment...

Despite significant advancements in screening, diagnosis, and treatment of non-small cell lung cancer (NSCLC), it remains the primary cause of cancer-related deaths globally. DNA damage is caused by the exposure to exogenous and endogenous factors and the correct functioning of DNA damage repair (DDR) is essential to maintain of normal cell circulation. The presence of genomic instability, which results from defective DDR, is a critical characteristic of cancer. The changes promote the accumulation of mutations, which are implicated in cancer cells, but these may be exploited for anti-cancer therapies...

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape...

In the 2023 series, we summarized the major clinical research advances in gynecologic oncology based on communications at the conference of Asian Society of Gynecologic Oncology Review Course. The review consisted of 1) Endometrial cancer: immune checkpoint inhibitor, antibody drug conjugates (ADCs), selective inhibitor of nuclear export, CDK4/6 inhibitors WEE1 inhibitor, poly (ADP-ribose) polymerase (PARP) inhibitors. 2) Cervical cancer: surgery in low-risk early-stage cervical cancer, therapy for locally advanced stage and advanced, metastatic, or recurrent setting; and 3) Ovarian cancer: immunotherapy, triplet therapies using immune checkpoint inhibitors along with antiangiogenic agents and PARP inhibitors, and ADCs...

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OBJECTIVE: The treatment for high risk or recurrent gestational trophoblastic neoplasia (GTN) is a highly toxic multi-agent chemotherapy. For patients with progressive or recurrent GTN, checkpoint inhibitors have demonstrated anti-tumor activity; however, identification of novel therapies for GTN remain an unmet need. Therefore, we sought to characterize the molecular landscape of GTN to identify potential therapeutic targets. METHODS: GTN samples were analyzed using a combination of molecular - next-generation sequencing (NGS) or whole exome sequencing (WES)- and protein- Immunohistochemistry (IHC) analyses...

Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision of replication for fast proliferation and increased genomic instability. To overcome the consequences of improper replication control, malignant cells frequently inactivate parts of their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other pathways which help to maintain replication fork stability (ATR-CHK1). This creates a dependency on the remaining DDR pathways, vulnerability to further destabilization of replication and synthetic lethality of DDR inhibitors with common oncogenic alterations such as mutations of TP53 , RB1 , ATM , amplifications of MYC , CCNE1 and others...

WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been thoroughly examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC and NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s...

Breast cancer arises from a series of molecular alterations that disrupt cell cycle checkpoints, leading to aberrant cell proliferation and genomic instability. Targeted pharmacological inhibition of cell cycle regulators has long been considered a promising anti-cancer strategy. Initial attempts to drug critical cell cycle drivers were hampered by poor selectivity, modest efficacy and haematological toxicity. Advances in our understanding of the molecular basis of cell cycle disruption and the mechanisms of resistance to CDK4/6 inhibitors have reignited interest in blocking specific components of the cell cycle machinery, such as CDK2, CDK4, CDK7, PLK4, WEE1, PKMYT1, AURKA and TTK...

In the era of targeted therapeutics, protein kinases like WEE1 have become pivotal drug targets, especially for cancer therapy. Utilizing a multi-faceted approach, our study adds fresh insights to this endeavour. We employed the t-SNE algorithm, combined with ECFP4 fingerprints, to analyse the molecular similarity between FDA-approved drugs and known clinical trial inhibitors. Our t-SNE analysis identified the closest clusters to known inhibitors and selected 11 FDA-approved drugs for further study. Using the DrugSpaceX platform, we generated analogues for these 11 FDA-approved drugs...

PURPOSE: WEE1 is a crucial kinase involved in the regulation of G2/M checkpoint within the cell cycle. This article aims to comprehensively review the existing knowledge on the implication of WEE1 as a therapeutic target in tumor progression and drug resistance. Furthermore, we summarize the current predictive biomarkers employed to treat cancer with WEE1 inhibitors. METHODS: A systematic review of the literature was conducted to analyze the association between WEE1 inhibition and cancer progression, including tumor advancement and drug resistance...

BACKGROUND: Indigofera suffruticosa Mill. is used as a folk medicine for treating patients with leukemia, however very little is known regarding the molecular mechanism of its anti-leukemic activity and the chemical profile of the active extract. The present study aimed to reveal the molecular effect of I. suffruticosa aerial parts extract (ISAE) on leukemia cells and its chemical constituents. METHODS: Cytotoxicity of ISAE were determined by resazurin viability assay, multitox - Glo multiplex cytotoxicity assay, and Annexin V staining assay...

Introduction: Recurrence signifies the primary mortality factor in patients suffering from endometrial cancer, with few efficacious treatments currently available for recurrent cases. This research investigates the anti-tumoral capacities of WEE1 inhibitors within the context of endometrial cancer, aiming to establish a novel therapeutic avenue for high recurrence-risk patients. Materials and methods: We evaluated WEE1 expression in endometrial cancer patients utilizing immunohistochemistry on paraffin-embedded tissue sections...

BACKGROUND: Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma...

Wee1 is a cell cycle regulator that phosphorylates Cdk1/Cdc2 and inhibits G2/M transition. Loss of Wee1 in fission yeast results in an early onset of mitosis. Interestingly, we found that cells lacking Wee1 require the functional spindle checkpoint for their viability. Genetic analysis indicated that the requirement is not attributable to the early onset of mitosis. Live-cell imaging revealed that some kinetochores are not attached or bioriented in the wee1 mutant. Furthermore, Mad2, a component of the spindle checkpoint known to recognize unattached kinetochores, accumulates in the vicinity of the spindle, representing activation of the spindle checkpoint in the mutant...

Breast and gynecological cancers are among the leading causes of death in women worldwide, illustrating the urgent need for innovative treatment options. We identified MYT1 as a promising new therapeutic target for breast and gynecological cancer using PandaOmics, an AI-driven target discovery platform. The synthetic lethal relationship of MYT1 in tumor cell lines with CCNE1 amplification enhanced this rationale. Through structure-based drug design, we developed a series of novel, potent, and highly selective inhibitors specifically targeting MYT1...

G2 /M cell cycle checkpoint protein WEE1 kinase is a promising target for inhibiting tumor growth. Although various WEE1 inhibitors have entered clinical investigations, their therapeutic efficacy and safety profile remain unsatisfactory. In this study, we employed a comprehensive virtual screening workflow, which included Schrödinger-Glide molecular docking at different precision levels, as well as the utilization of tools such as MM/GBSA and Deepdock to predict the binding affinity between targets and ligands, in order to identify potential WEE1 inhibitors...