MK-8776 / Merck (MSD) - LARVOL DELTA

Decitabine Synergizes with Replication Checkpoint Inhibitors in TP53-Mutated Acute Myeloid Leukemia (ASH 2024) - "Prior reports suggest that DNA methyltransferase inhibitors (DNMTi), such as decitabine and azacitidine, form covalent DNA-DNMT1 adducts and invoke a DNA damage response (DDR) characterized by activation of the ATR-CHK1 pathway, including in TP53MT AML samples...Similar results were obtained from decitabine (EC50 = 300 ± 100 nM) and ceralasertib (CI 0.54), adavosertib (CI 0.67), MK-8776 (CI 0.52), and prexasertib (CI 0.81) in annexin V assays.These combinations were further evaluated (SubG1 assays) in an isogenic pair of Molm13 and Molm13 TP53-/- cell lines...Combination treatment was antagonistic with ceralasertib (CI 2.2), additive with prexasertib (CI 1.0), and synergistic with adavosertib (CI 0.88).ConclusionsIn multiple cell lines and diverse primary AML samples, decitabine activated the ATR-CHK1 DDR pathway and synergized with ATRi, CHK1/2i, and WEE1i. Amongst these, only the combination of decitabine plus adavosertib exhibited synergy across all three models,..."

Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • DNMT1

ATP6V0A4 as a novel prognostic biomarker and potential therapeutic target in oral squamous cell carcinoma. (PubMed, BMC Oral Health) - "ATP6V0A4 may serve as a novel prognostic biomarker and potential therapeutic target in oral squamous cell carcinoma."

Biomarker • IO biomarker • Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • ATP6V0A4

Application of Biological Modifiers to a Multiplexed, Human Cell-Based DNA Damage Assay Provides Mechanistic Information on Genotoxicity and Molecular Targets. (PubMed, Environ Mol Mutagen) - "Cells were exposed in 96-well plates in the presence and absence of each of four modifying agents at one optimized concentration: talazoparib (PARP inhibitor), MK-8776 (CHK1 inhibitor), AZD-7648 (DNA-PK inhibitor), or a cocktail of reactive oxygen species scavengers. Unsupervised hierarchical clustering of the collective potency metrics for various combinations of biomarkers showed that clastogens with similar genotoxic mechanisms grouped together. Overall, this study shows that in combination with biological response modifiers, MultiFlow and In Vitro MicroFlow biomarkers can provide mechanistic insights into chemical-induced genotoxicity."

Journal

Decitabine (DAC) induces a DNA damage response (DDR) and synergizes with replication checkpoint inhibitors in acute myeloid leukemia (AML) (AACR 2025) - "(nM)Molm13 (TP53WT)Molm13 (TP53-/-)U937 (TP53G187fs*/-)KG1a (TP53V225fs*/-)Primary AML (TP53WT orTP53MT)UnitsDecitabineDNMT16.25 – 20025 ± 11350 ± 260310 ± 1806.1 ± 1.6NDEC50, nM (mean, SD)CeralasertibATR250 – 5000.93 (0.66 – 1.24)0.90 (0.84 – 0.96)0.15 (0.08 – 0.21)0.74 (0.63 – 1.02)0.66 (0.43 – 2.43)CI with decitabine (median, IQR) CamonsertibATR10 – 1000.27 (0.19 – 0.59)0.24 (0.22 – 0.34)0.34 (0.21 – 0.39)NDNDPrexasertibCHK1/21.0 – 6.00.89 (0.82 – 1.06)0.78 (0.68 – 0.90)0.95 (0.93 – 1.08)ND0.88 (0.29 – 1.28)MK-8776CHK1250 – 1,0000.57 (0.48 – 0.80)0.76 (0.73 – 1.19)0.89 (0.57 – 1.39)NDNDRabusertibCHK1600 – 1,000NDNDND0.51 (0.48 – 0.56)NDAdavosertibWEE1100 – 4000.70 (0.63 – 1.11)0.99 (0.78 – 1.14)0.67 (0.60 – 0.74)0.67 (0.37 – 0.93)0.65 (0.43 – 0.88)Table 1. U937 data were replicated using annexin V. Prexasertib showed no activity in KG1a cells (suggesting drug efflux) requiring the use of the alternate CHK1 inhibitor, rabusertib. Abbreviations: ATR,..."

Checkpoint inhibition • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ANXA5 • ATR • DNMT1

CDK2 activation mediates response of acute myeloid leukemia to CHK1, ATR and WEE1 inhibitors (AACR 2025) - "Here we have comprehensively characterized the processes that occur between the interruption of replication checkpoints and leukemic cell death in these sensitive cells versus cells selected for RCM resistance. Using the CHK1 inhibitors MK8776 and prexasertib, ATR inhibitors berzosertib and ceralasertib, and WEE1 inhibitor adavosertib as paradigm drugs, we examined signaling in two AML cell lines, U937 and THP.1, that were selected for CHK1 inhibitor resistance, examined cross-resistance patterns, and assessed the biochemical basis for leukemic cell death. Our findings reveals critical new insights into the factors that influence the response to CHK1 inhibitors in AML. Importantly, we found no evidence of cross-resistance to inhibitors of other replication checkpoint proteins, enabling alternative options."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CDC25A • CDK2 • CHEK1 • GNRP • TNFA • TP53

Targeting Chk1 and Wee1 kinases enhances radiosensitivity of 2D and 3D head and neck cancer models to X-rays and low/high-LET protons. (PubMed, Cell Death Dis) - "Here, we have analysed the response of head and neck squamous cell carcinoma (HNSCC) cell lines, spheroids and patient-derived organoids to X-rays and proton beam therapy (PBT) in the presence of either a Chk1 (MK-8776) or a Wee1 (MK-1775) inhibitor. We demonstrate that inhibitors of Chk1 or Wee1 can significantly enhance the radiosensitivity of both 2D and 3D models of HNSCC to X-rays and PBT (performed at both low and high ionisation densities), and that this effect is caused through abrogation of the G2/M checkpoint causing the persistence of DSBs. Our results therefore suggest that targeting Chk1 and Wee1 kinases in combination with X-rays and PBT could represent a promising therapeutic avenue to enhance the clinical efficacy of HNSCC treatment."

Journal • Preclinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CHEK1

MK-8776 and Olaparib Combination Acts Synergistically in Hepatocellular Carcinoma Cells, Demonstrating Lack of Adverse Effects on Liver Tissues in Ovarian Cancer PDX Model. (PubMed, Int J Mol Sci) - "No changes were observed in corresponding liver tissues using Ki-67 and pCHK staining, which indicates the absence of metastases and a hepatotoxic effect. Thus, our results indicate that the dual inhibition of PARP and CHK1 may prove to be a promising therapeutic approach in the treatment of primary HCC as well as OC tumors without the risk of liver metastases, especially in patients with olaparib-resistant tumor profiles."

Adverse events • Journal • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Ovarian Cancer • Solid Tumor • CASP3 • CASP7

Molecular mechanisms restoring olaparib efficacy through ATR/CHK1 pathway inhibition in olaparib-resistant BRCA1/2MUT ovarian Cancer models. (PubMed, Biochim Biophys Acta Mol Basis Dis) - "Olaparib-resistant xenografts were treated with olaparib, ATR inhibitor (ATRi, ceralasertib), CHK1 inhibitor (CHK1i, MK-8776) or their combinations. Our collective findings indicate that ATR/CHK1 pathway inhibition restores the olaparib efficacy in resistant BRCA1/2MUT high-grade serous OC, highlighting promising approach for olaparib rechallenge of non-responsive patients. Uncovered mechanisms might improve our understanding of acquisition and overcoming resistance to olaparib in ovarian cancer."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor • ABCB1 • BRCA1 • BRCA2 • TP53BP1 • VIM

Loss of heterozygosity of CYP2D6 enhances the sensitivity of hepatocellular carcinomas to talazoparib. (PubMed, EBioMedicine) - "Exploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

Methylation of FAM110C is a synthetic lethal marker for ATR/CHK1 inhibitors in pancreatic cancer. (PubMed, J Transl Int Med) - "Loss of FAM110C expression sensitizes PDAC cells to VE-822 (an ATR inhibitor) and MK-8776 (a CHK1 inhibitor). FAM110C methylation is a potential diagnostic and prognostic marker in PDAC, and its epigenetic silencing sensitizes PDAC cells to ATR/CHK1 inhibitors."

Journal • Synthetic lethality • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • HMGB1

Precise nano-system-based drug delivery and synergistic therapy against androgen receptor-positive triple-negative breast cancer. (PubMed, Acta Pharm Sin B) - "HMnE&M@H repressed tumor growth more obviously than the simple addition of enzalutamide and MK-8776 without a carrier. Collectively, our study elucidated the synergy of enzalutamide and MK-8776 in TNBC and developed a novel tumor-targeted nano drug delivery system HMnE&M@H, providing a potential therapeutic approach for the treatment of TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AR

Characterization of Mitoribosomal Small Subunit unit genes related immune and pharmacogenomic landscapes in renal cell carcinoma. (PubMed, IUBMB Life) - "Through in silico screening of 2183 drug targets and 1646 compounds, we identified two targets (RRM2 and OPRD1) and eight agents (AZ960, carmustine, lasalocid, SGI-1776, AZD8055_1059, BPD.00008900_1998, MK.8776_2046, and XAV939_1268) with potential therapeutic implications for high-MRPScore patients. Indeed, a high MRPScore profile appears to elevate the risk of tumor progression and mortality, potentially through its influence on immune regulation. This suggests that the MRPS-related risk model holds promise as a prognostic predictor and may offer novel insights into personalized therapeutic strategies."

Biomarker • IO biomarker • Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • RRM2

Transcriptional Differential Analysis of Nitazoxanide-Mediated Anticanine Parvovirus Effect in F81 Cells. (PubMed, Viruses) - "Canine parvovirus (CPV) is a single-stranded DNA virus that can cause typical hemorrhagic enteritis, and it is one of the common canine lethal viruses. Moreover, when the cell cycle was regulated with cell cycle checkpoint kinase 1 (Chk1) inhibitor MK-8776 or Prexasertib HCl, both inhibitors inhibited the CPV. In summary, the transcriptome differential analysis results presented in this paper lay the foundation for further research on the molecular mechanism and potential targets of NTZ anti-CPV."

Journal • Gastrointestinal Disorder • Hematological Disorders

Inhibition of Chk1 stimulates cytotoxic action of platinum-based drugs and TRAIL combination in human prostate cancer cells. (PubMed, Biol Chem) - "Here we newly demonstrate that pharmacological inhibition of Chk1 using potent and selective inhibitor SCH900776, currently profiled in phase II clinical trials, significantly enhances cytotoxic effects of the combination of platinum-based drugs (cisplatin or LA-12) and TRAIL (tumor necrosis factor-related apoptosis inducing ligand) in human prostate cancer cells. The triple drug combination-induced cytotoxicity was partially enhanced by siRNA-mediated Mcl-1 silencing. Our findings suggest that targeting Chk1 may be used as an efficient strategy for sensitization of prostate cancer cells to killing action of platinum-based chemotherapeutic drugs and TRAIL."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CHEK1

Harnessing machine learning to find synergistic combinations for FDA-approved cancer drugs. (PubMed, Sci Rep) - "Analysis highlighted Gemcitabine, MK-8776 and AZD1775 as frequently synergizing across cancer types. This machine learning framework provides a valuable approach to uncover more effective multi-drug regimens."

FDA event • Journal • Machine learning • Colorectal Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor

Integrative modeling uncovers p21-driven drug resistance and prioritizes therapies for PIK3CA-mutant breast cancer (NPJ Precis Oncol, Nature) - "Functionally, high p21 levels favored repair of BYL719-induced DNA damage and bypass of the associated cellular senescence. Importantly, targeted inhibition of the check-point inhibitor CHK1 with MK-8776 effectively caused death of p21-high T47D cells, thus establishing a new vulnerability of BYL719-resistant breast cancer cells."

Preclinical • Breast Cancer

Integrative modeling uncovers p21-driven drug resistance and prioritizes therapies for PIK3CA-mutant breast cancer (NPJ Precis Oncol, Nature) - "Functionally, high p21 levels favored repair of BYL719-induced DNA damage and bypass of the associated cellular senescence. Importantly, targeted inhibition of the check-point inhibitor CHK1 with MK-8776 effectively caused death of p21-high T47D cells, thus establishing a new vulnerability of BYL719-resistant breast cancer cells."

Preclinical • Breast Cancer

Integrative modeling uncovers p21-driven drug resistance and prioritizes therapies for PIK3CA-mutant breast cancer. (PubMed, NPJ Precis Oncol) - "Importantly, targeted inhibition of the check-point inhibitor CHK1 with MK-8776 effectively caused death of p21-high T47D cells, thus establishing a new vulnerability of BYL719-resistant breast cancer cells. Together, our integrated studies uncover hidden molecular mediators causing resistance to PI3Kα inhibition and provide a framework to prioritize combination therapies for PI3K-mutant breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • CDKN1A • CHEK1 • PIK3CA

Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2 ovarian cancer cells. (PubMed, Sci Rep) - "Antitumor activity of olaparib alone or combined with an ATR inhibitor (ATRi, ceralasertib) or CHK1 inhibitor (CHK1i, MK-8776) was evaluated in OC cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Overall, the addition of ATRi or CHK1i to olaparib effectively overcomes resistance to PARPi exerting anti-proliferative effect in BRCA2 olaparib-resistant OC cells and alters expression of DDR-related proteins. These new molecular insights into cellular response to olaparib combined with ATR/CHK1 inhibitors might help improve targeted therapies for olaparib-resistant OC."

Journal • Oncology • Ovarian Cancer • Solid Tumor • ABL1 • BRCA2 • CASP3 • CASP7 • CDKN1A

Identification of aneuploidy-related gene signature to predict survival in head and neck squamous cell carcinomas. (PubMed, Aging (Albany NY)) - "We classified 3 molecular subtypes for HNSC patients and established an ARS prognostic model, which offered a prospective direction for prognosis in HNSC."

Gene Signature • IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CCR4 • CCR7 • CD79A • ICOS • IL1R1 • ZAP70

Chronic treatment with ATR and CHK1 inhibitors does not substantially increase the mutational burden of human cells. (PubMed, Mutat Res) - "To investigate this question, we performed chronic long-term treatments of TP53-depleted human cancer cells with ATR and CHK1 inhibitors (ATRi, AZD6738/ceralasertib and CHK1i, MK8776/SCH-900776). Interestingly, ATR inhibition did induce a slight increase in closely-spaced mutations, a feature previously attributed to translesion synthesis DNA polymerases. The results suggest that ATRi and CHK1i do not have substantial mutagenic effects in vitro when used as standalone agents."

Journal • Tumor mutational burden • Oncology • TMB • TP53

Inhibition of checkpoint kinase prevents human oocyte apoptosis induced by chemotherapy and allows enhanced tumour chemotherapeutic efficacy. (PubMed, Hum Reprod) - "These findings highlight the therapeutic potential of CHEK1/2 inhibitors as a complementary strategy for preserving fertility in female cancer patients."

Journal • Oncology • Transplantation • CHEK1 • CHEK2

The clinically relevant CHK1 inhibitor MK-8776 induces the degradation of the oncogenic protein PML-RARα and overcomes ATRA resistance in acute promyelocytic leukemia cells. (PubMed, Biochem Pharmacol) - "The current treatment approach for APL involves differentiation therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Overall, the ability of MK-8776 to induce PML-RARα degradation and stimulate differentiation of immature APL cancer cells into more mature forms recapitulates the concept of differentiation therapy. Considering the in vivo tolerability of MK-8776, it will be relevant to evaluate its potential clinical benefit in APL patients resistant to standard ATRA/ATO therapy, as well as in patients with other forms of acute leukemias."

Journal • Acute Promyelocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CASP3 • ITGAM • PML • RARA

Combined Aurora Kinase A and CHK1 Inhibition enhances radiosensitivity of triple-negative breast cancer through induction of apoptosis and mitotic catastrophe associated with excessive DNA damage. (PubMed, Int J Radiat Oncol Biol Phys) - "Different TNBC cell lines were treated with AURKA inhibitor (AURKAi, MLN8237) and CHK1i (CHK1i, MK8776). Additionally, dual inhibition of AURKA and CHK1 synergistically enhanced radiosensitivity in MDA-MB-231 xenografts. Moreover, we detected that both CHEK1 and AURKA were overexpressed in TNBC patients and negatively correlated with patients' survival Our findings suggested that AURKAi in combination with CHK1i enhanced TNBC radiosensitivity in preclinical models, potentially providing a novel strategy of precision treatment for patients with TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AURKA

PARP and ATR/CHK1 inhibitors employment call out ovarian cancer cell death through premature mitotic entry and genomic instability. (EACR 2023) - "Combining olaparib with ATR/CHK1 inhibitors increases its effectiveness and may be a new opportunity for more effective ovarian cancer therapy.Material and MethodsWe examined efficacy of PARPi in combination with DNA damage response pathway proteins inhibitors - ATR (AZD6738, ATRi) and CHK1(MK8776, CHK1i) kinases in BRCAMUT (PEO-1) and BRCAWT (SKOV-3 and OV-90) cells. ATR and CHK1 inhibitors provoke premature mitotic entry, leading to genomic instability and ultimately cell death. This research was funded by the National Science Centre, Poland, grant number: Sonata Bis 2019/34/E/NZ7/00056."

Oncology • Ovarian Cancer • Solid Tumor • BRCA