adavosertib (AZD1775) / AstraZeneca, Merck (MSD) - LARVOL DELTA

Two Phase II Trials of Adavosertib, a Wee1 Inhibitor with Docetaxel or Carboplatin plus Pemetrexed in Non-small-cell Lung Cancer. (PubMed, Target Oncol) - P2 | "Both studies terminated early; the recurrent study after an interim analysis showed increased toxicity and limited efficacy, and the first-line study after a change in first-line standard of care."

Journal • P2 data • Fatigue • Hematological Disorders • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Neutropenia • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Thrombocytopenia

CDK7 inhibition mitigates AZD1775 resistance via chromatin reprogramming in Myc-MB (WFNOS 2025) - "These findings suggest that THZ1 may reverse adaptive chromatin reorganization, sensitizing resistant MB cells to AZD1775 and enhancing the overall therapeutic response.Future studies will investigate the potential of combining CDK7 inhibitors with other epigenetic modulators to further disrupt resistance mechanisms and improve treatment outcomes in aggressive MB subtypes, particularly Group 3 MB. This approach offers a promising avenue for overcoming therapeutic resistance and advancing precision medicine in medulloblastoma."

Brain Cancer • Medulloblastoma • Pediatrics • Solid Tumor • MYC

Investigating the role of CDKN2B in glioblastoma (WFNOS 2025) - "We generated double knockouts of CDKN2A and CDKN2B in M059K cells and obtained modest but significant increases in sensitivity to both the CHK1/2 inhibitor Prexasertib and the WEE1 inhibitor Adavosertib, another inhibitor of the G2/M checkpoint. This demonstrated that the additional loss of CDKN2B along with CDKN2A loss and TP53 mutation was necessary to sensitize these cells to G2/M checkpoint inhibition. This work suggests that inactivation of both CDKN2A and CDKN2B is necessary to accurately model this homozygous deletion."

Brain Cancer • Glioblastoma • Glioma • Solid Tumor • CDKN2A • CDKN2B • CHEK2

Efficacy of Wee1 G2 Checkpoint Kinase and Mouse Double Minute 2 Homolog Inhibitors in Gastrointestinal Stromal Tumors Determined by p53 Status. (PubMed, Oncol Res) - "The efficacy of the mouse double minute 2 homolog (MDM2) inhibitor (HDM201) and the Wee1 G2 checkpoint kinase (Wee1) inhibitor (adavosertib) was confirmed in both p53 wild-type (p53 WT) and p53 mutant (p53 MT) GIST cells. Our results highlight the importance of p53 status in guiding GIST treatment. p53 WT tumors respond to MDM2 inhibitors, while p53 MT tumors show greater sensitivity to Wee1 inhibitors, supporting p53 pathway targeting as a promising strategy for GIST patients."

Journal • Preclinical • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • CDK1 • CDKN1A • PDGFRA • TP53

Plasma exosomal lncRNA-related signatures define molecular subtypes and predict survival and treatment response in hepatocellular carcinoma. (PubMed, Front Immunol) - "Risk model analysis predicted differential treatment responses: low-risk patients exhibited superior anti-PD-1 immunotherapy responses, whereas high-risk patients showed increased sensitivity to DNA-damaging agents (e.g., the Wee1 inhibitor MK-1775) and sorafenib. Plasma exosomal lncRNAs enable robust molecular subtyping, accurate prognostic stratification, and treatment response prediction in HCC. The ERG-centric classification system and validated 6-gene risk model provide clinically actionable tools for precision oncology."

Biomarker • IO biomarker • Journal • Tumor mutational burden • Hepatocellular Cancer • Oncology • Solid Tumor • ADH1C • CTLA4 • KIF20A • MCM4 • NDRG1 • PD-L1 • RECQL4 • TGFB1 • TMB • TTN

ACR-2316 is a novel, differentiated, clinical-stage WEE1/PKMYT1 inhibitor designed by Acrivon's Generative Phosphoproteomics AP3 Platform for optimal pro-apoptotic pathway effects in tumor cells resulting in superior preclinical activity (AACR-NCI-EORTC 2025) - "In cellular TE assays, ACR-2316 displayed more potent WEE1 TE than all benchmark WEE1 inhibitors (azenosertib, adavosertib, Debio0123), while simultaneously targeting MYT1... WEE1 inhibitor-induced MYT1 activation constitutes a resistance mechanism that may limit the clinical efficacy of WEE1 inhibition. ACR-2316 is a potent, selective WEE1/MYT1 inhibitor that displays superior preclinical efficacy via its differentiated profile optimized by AP3 pathway-based structure-activity relationships in the intact cell. Acrivon's ongoing Phase 1 ACR-2316 monotherapy trial in solid tumors has already demonstrated clinical activity during dose escalation prior to reaching Recommended Phase 2 Dose."

Preclinical • Tumor cell • Oncology • Solid Tumor • BRAF • CDK1 • CDK2 • PKMYT1 • PLK1

Biomarker analyses of WEE1 inhibition in patients with refractory CCNE1 amplified solid tumors (AACR-NCI-EORTC 2025) - P2 | "Biomarker analyses using IHC, RNA-seq and WES showed WEE1 inhibition induced significantly expression of the immunosuppressive genes. Patients with immune-desert TME at baseline or on treatment responded poorly to WEE1 inhibition, supporting further exploration of WEE1 inhibition in combination with TME-modulated immunotherapy for the treatment of patients with CCNE1 amplified malignancies."

Biomarker • Clinical • IO biomarker • Oncology • Solid Tumor • CCNE1 • FKBP5 • MB • TGFB1 • TP53 • TSC22D3

Inducing mitotic catastrophe in high replicative stress castration resistant prostate cancer through inhibition of WEE1 (AACR-NCI-EORTC 2025) - " We determined the half-maximal inhibitory concentrations (IC₅₀) of two WEE1 inhibitors, AZD1775 (adavosertib) and ZN-c3 (azenosertib), in a panel of LNCaP-derived prostate cancer cell lines: LNCaP (parental), LNCaP-AR (androgen receptor amplification), and LNCaP-DKO (RB1 and TP53 double knockout). Our findings demonstrate that mCRPC models with G1 checkpoint mutations and inherently high replicative stress are more susceptible to WEE1i, revealing a potential predictive biomarker that can be leveraged for therapeutic efficacy."

Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CDK1 • RB1 • TP53

Testing the Sequential Combination of the Anti-cancer Drugs Olaparib Followed by Adavosertib (AZD1775) in Patients With Advanced Solid Tumors With Selected Mutations and PARP Resistance, STAR Study (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Sep 2025 ➔ Sep 2026

Trial completion date • Oncology • Solid Tumor • BRCA1 • BRCA2 • BRIP1 • CD4 • FANCA

Preclinical evaluation of the antitumoral efficacy of Wee1 inhibitor AZD1775 in adrenocortical carcinoma. (PubMed, Pharmacol Res) - "Current therapy for advanced adrenocortical carcinoma (ACC) is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane), but its efficacy is limited and new approaches are needed. Interestingly, Myt1 increase after AZD1775 treatment in primary ACC cells was reverted by EDP-M cotreatment. Overall, our data in in vitro and in vivo preclinical ACC models support AZD1775 as a promising ACC therapeutic option, and its combination with EDP-M as a useful strategy to enhance drug efficacy, reduce cortisol secretion, prevent drug resistance and minimize side effects by reducing the therapeutic dosage."

Journal • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • PKMYT1

NCI-MATCH: Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) (clinicaltrials.gov) - P2 | N=6452 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Biomarker • Trial completion date • Trial primary completion date • Bladder Cancer • Brain Cancer • Breast Cancer • Cervical Cancer • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Esophageal Cancer • Gastric Cancer • Genito-urinary Cancer • Glioblastoma • Glioma • Head and Neck Cancer • Hematological Malignancies • Hormone Receptor Positive Breast Cancer • Kidney Cancer • Liver Cancer • Lung Cancer • Lymphoma • Melanoma • Multiple Myeloma • Oncology • Ovarian Cancer • Pancreatic Cancer • Prostate Cancer • Refractory Ovarian Cancer • Renal Cell Carcinoma • Skin Cancer • Solid Tumor • Thyroid Gland Carcinoma • Uterine Cancer • CD4 • MSI

WEE1 inhibitors synergise with mRNA translation defects via activation of the kinase GCN2. (PubMed, Nat Commun) - "Using a pooled CRISPRi screen, we identify GSPT1 and ALKBH8 as factors whose depletion confer hypersensitivity to the WEE1 inhibitor, AZD1775...This dual mechanism highlights opportunities for combination therapies, such as pairing WEE1 inhibitors with agents targeting the mRNA translation machinery. This study also underscores the need for more precise WEE1 targeting strategies to mitigate off-target effects, with implications for optimising the therapeutic potential of WEE1 inhibitors."

Journal • Immunology • Oncology • Targeted Protein Degradation • GSPT1

Prostate Cancer Biomarker Enrichment and Treatment Selection (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Jun 2025 ➔ Oct 2024

Biomarker • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Development of a prognostic risk model for predicting biochemical recurrence-free survival in patients with prostate cancer based on lysine acetylation. (PubMed, Transl Androl Urol) - "Drugs such as cisplatin, MK-1775, and ulixertinib were identified as potential therapeutic agents for PCa. Five BCR-free-related prognostic genes were identified as potential therapeutic targets. Additionally, a BCR-free-related prognostic risk model was developed, offering a robust tool for predicting BCR-free survival in patients with PCa."

Journal • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PLS3

Combined inhibition of WEE1 by AZD1775 synergistically enhances CX-5461 mediated DNA damage and induces cytotoxicity in glioblastoma. (PubMed, Tissue Cell) - "Consequently, these results suggest that CX-5461 inhibited GBM progression by stabilizing G4, causing replication stress and exacerbating DNA damage. Targeting G4 structures, especially when combined with checkpoint inhibitors, provides a hopeful therapeutic approach to improve the effectiveness of GBM therapy."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Testing AZD1775 in Advanced Solid Tumors That Have a Mutation Called SETD2 (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Aug 2025 ➔ Mar 2026 | Trial primary completion date: Aug 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • SETD2

Combination of WEE1 Inhibitor and Vitamin K2 Enhances Therapeutic Efficacy in Chronic Myeloid Leukemia. (PubMed, Cancer Innov) - "A combined regimen of MK-1775 and VK2 markedly decreased colony growth, disrupted mitochondrial membrane potential, and increased death in CML cells, including those resistant to TKIs. The results suggest that a combination of MK-1775 and VK2 represents a potentially effective treatment strategy for CML, especially in drug-resistant cases."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • ABL1 • CASP3 • CASP7 • PKMYT1

WEE1 inhibitor exerts synergistic effect with KRAS G12C inhibitor via MYBL2-RRM2 axis in KRASG12C-mutant lung cancer. (PubMed, Cell Death Dis) - "Here, we demonstrate that the WEE1 kinase inhibitor (WEE1i), Adavosertib, can sensitize the effect of G12Ci through the MYBL2-RRM2 axis, which is associated with poor prognosis in lung cancer...We also observed marked effects of the combination therapy in tumor xenografts models. Collectively, these results uncover the WEE1 kinase inhibitors, some of which are available clinically, as effective enhancers for G12Ci therapy."

Journal • Lung Cancer • Oncology • Solid Tumor • KRAS • MYBL2 • RRM2

WEE1 inhibitor exerts synergistic effect with KRAS G12C inhibitor via MYBL2-RRM2 axis in KRASG12C-mutant lung cancer (Nature) - "Here, we demonstrate that the WEE1 kinase inhibitor (WEE1i), Adavosertib, can sensitize the effect of G12Ci through the MYBL2-RRM2 axis, which is associated with poor prognosis in lung cancer. Overexpressing the MYBL2-RRM2 axis or supplementing the products of the RRM2 enzyme, dNTPs/dNs, can partially reverse this synergistic inhibitory effect. We also observed marked effects of the combination therapy in tumor xenografts models. Collectively, these results uncover the WEE1 kinase inhibitors, some of which are available clinically, as effective enhancers for G12Ci therapy."

Preclinical • Lung Cancer

EAY131-Z1I: Testing AZD1775 as a Potential Targeted Treatment in Cancers With BRCA Genetic Changes (MATCH-Subprotocol Z1I) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2025 ➔ Dec 2026 | Trial primary completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Trial primary completion date • Breast Cancer • Hematological Malignancies • HER2 Negative Breast Cancer • Lymphoma • Multiple Myeloma • Oncology • Ovarian Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2

Evaluation of pleural mesothelioma sensitivity to targeted DNA damage response inhibitors (EACR 2025) - "Long-term cell proliferation assays lasting 7 to 15 days were conducted using various concentrations of the following DDR inhibitors: berzosertib and ceralasertib (ATR inhibitors), AZD0156 (an ATM inhibitor), olaparib (a PARP inhibitor), adavosertib (a WEE1 inhibitor), and rabusertib (a CHEK1 inhibitor). These results represent a preclinical rationale for designing clinical trials with DDR for MPM patients."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Sarcoma • Solid Tumor • BAP1 • RAD51

Targeting the DNA damage response prevents regrowth of colorectal peritoneal metastasis-derived organoids following treatment with mitomycin C. (EACR 2025) - "We tested whether inhibitors of the DNA damage response (DDR) could prevent recurrence in an in vitro HIPEC model.Material and Peritoneal metastasis-derived organoids (PMDOs; n=10) were treated with inhibitors of ATR (berzosertib, ceralasertib, elimusertib), CHK1 (rabusertib), and WEE1 (adavosertib) alone, and in combination with MMC, oxaliplatin, or irinotecan. PMDOs can be completely eradicated if MMC treatment is followed by inhibition of ATR or other DDR kinases. DDR inhibitors may, therefore, have value in the adjuvant treatment of peritoneal metastases following CRS-HIPEC."

Colorectal Cancer • Oncology • Solid Tumor • CHEK1

Phase 2 study of Wee1 inhibitor adavosertib in recurrent uterine carcinosarcoma. (PubMed, Gynecol Oncol Rep) - "In this phase II trial of 9 patients with TP53-mutated UCS, adavosertib demonstrated limited activity. However, future studies of molecular alterations and combinatorial strategies continue to be of interest in UCS with limited treatment options."

Journal • P2 data • Carcinosarcoma • Fatigue • Oncology • Sarcoma • Solid Tumor • TP53

Targeting WEE1 and asciminib suppresses ABL-tyrosine kinase inhibitor-resistant chronic myeloid leukemia cells. (PubMed, Discov Oncol) - "The combination of asciminib and WEE1 inhibition demonstrated greater efficacy than either drug alone, suggesting a novel therapeutic strategy for treating CML. These findings provide insights into overcoming TKI resistance and highlight a promising approach for future clinical applications."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ABL1 • PKMYT1 • WEE1

Solubility Modeling for Key Organic Compounds Used in Adavosertib (Anticancer API) Manufacturing. (PubMed, ACS Omega) - "The present paper has thus employed the Non-Random Two-Liquid Segment Activity Coefficient (NRTL-SAC) model to describe the solubility of six organic compounds used in the production of an experimental anticancer drug, Adavosertib (specifically: AZD1775 Adavosertib Maleate, AZD1775 Aniline Maleate, AZD1775 Nitropip, AZD1775 Hydroxymethylsulfanyl, AZD1775 Bromopyridine.HBr, and AZD1775 Pyrimidine). The NRTL-SAC model has also been employed to estimate the melting temperature and enthalpy of fusion of these compounds, circumventing various difficulties arising in direct measurements (e.g., endothermic/exothermic phenomena near the melting point)."

Journal • Oncology