rabusertib (LY 2603618) / Eli Lilly - LARVOL DELTA

The miR-195-5p/CHEK1 interaction in luminal breast carcinoma: Role in progression and chemoresistance (ESMO-BC 2025) - "Additionally, we assessed the effect of CHEK1 inhibition using miR-195-5p and the Chk1 chemical inhibitor rabusertib (LY2603618) on doxorubicin cytotoxicity through a cell viability assay. High level of CHEK1 expression was associated with shorter RFS in luminal BC patients treated with adjuvant chemotherapy, and the association was more significant in patients with luminal A subtype. In summary, our findings demonstrate the ability of miR-195-5p to inhibit CHEK1 expression in vitro, highlighting the clinical relevance of CHEK1 expression and its inhibition for prognosis and treatment strategies in luminal BC. This study was supported by the Czech Health Research Council grant no. NU22-08-00281."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CCNE1 • CDC25A • CHEK1 • ER • GNRP • MIR195

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

Targeting Metabolic and Epigenetic Vulnerabilities in Glioblastoma with SN-38 and Rabusertib Combination Therapy. (PubMed, Int J Mol Sci) - "A significant obstacle in treating GBM is the expression of O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that reduces the efficacy of the standard alkylating agent, temozolomide, in about 50% of patients. Reduced intermediates of the glutathione cycle indicated increased cellular stress following combinatorial treatment. Overall, the combination of SN-38 and rabusertib synergistically disrupts metabolites associated with epigenetic adaptations, leading to cytotoxicity independent of O6-methylguanine-DNA methyltransferase status, thereby underpinning this combination as a promising candidate for combinatorial therapy in GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Metabolic Disorders • Oncology • Solid Tumor • CHEK1

Proactive therapeutic drug monitoring and vedolizumab dose optimization in children with inflammatory bowel disease. (PubMed, J Pediatr Gastroenterol Nutr) - "Proactive TDM and early dose optimization with vedolizumab may improve drug durability and clinical outcomes in pediatric patients with IBD."

Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Oncology • Pediatrics • Ulcerative Colitis • TNFA

Metronomic dosing of ovarian cancer cells with the ATR inhibitor AZD6738 leads to loss of CDC25A expression and resistance to ATRi treatment. (PubMed, Gynecol Oncol) - "We show that metronomic dosing of ovarian cancer cells with AZD6738 results in resistance to ATR/ Chk1 inhibitors, that loss of CDC25A expression represents a mechanism of resistance to ATRi treatment in ovarian cancer cells and identify several circulating biomarker candidates of CDC25A low, AZD6738-resistant ovarian cancer cells."

Journal • Ataxia • Gynecologic Cancers • Immunology • Movement Disorders • Oncology • Ovarian Cancer • Primary Immunodeficiency • Solid Tumor • APOA1 • APOE • CDC25A • GNRP

Cytotoxicity of curcumin against CD44 prostate cancer cells: Roles of miR-383 and miR-708. (PubMed, Avicenna J Phytomed) - "The cytotoxicity of curcumin against CD44 cells (IC 40.30±2.32 μM) was found to be greater than that against CD44 cells (IC 83.31±2.91 μM)...Our findings indicate that curcumin, by promoting the expression of tumor suppressors, miR-383-5p and miR-708-5p, and inhibiting their target genes, induced its cytotoxicity against CD44 PC cells. We trust that curcumin could be established as a promising adjuvant therapy to current PC treatment options following more research in clinical settings."

Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • ANXA5 • LDHA • MIR383 • MIR708

Inhibition of RRM2 radiosensitizes glioblastoma and uncovers synthetic lethality in combination with targeting CHK1. (PubMed, Cancer Lett) - "Collectively, our results suggest RRM2 is a promising therapeutic target for GBM, and targeting RRM2 with triapine sensitizes GBM cells to radiation and independently induces synthetic lethality of GBM cells with CHK1 inhibition. Our findings suggest combining triapine with radiation or rabusertib may improve therapeutic outcomes in GBM."

Combination therapy • Journal • Synthetic lethality • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CHEK1 • RRM2

Targeting ribonucleotide reductase subunit 2 (RRM2) to radio-sensitize glioblastoma (AACR 2023) - "Purpose: Despite aggressive multimodality treatments, the median survival of glioblastoma (GBM) remains within the range of 12-15 months after diagnosis with standard-of-care surgery, radiation therapy (RT) and temozolomide (TMZ)...We further investigated whether CHK1 inhibition with LY2603618-Rabusertib could abrogate the replication stress induced expression of RRM2. RRM2 is significantly higher expressed in GBM compared to non-tumor tissues (p<0.0001 in both TCGA and Rembrandt datasets), and higher RRM2 expression is significantly associated with higher tumor grade (p<0.0001 in CGGA and p=0.001 in Rembrandt datasets) and worse overall survival (p=0.014 in CGGA dataset)... These results indicate that RRM2 is upregulated and important for GBM survival after radiation. Moreover, RRM2 inhibition with triapine effectively sensitizes GBM tumors to radiation in vitro and in vivo. Our findings suggest that triapine warrants clinical testing with radiation."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • H2AX • RRM2

Performance of discs, sensititre EUMDROXF microplates and MTS gradient strips for the determination of the susceptibility of multidrug resistant Pseudomonas aeruginosa to cefiderocol. (PubMed, Clin Microbiol Infect) - "Determination of cefiderocol susceptibility in MDR P. aeruginosa clinical strains by Sensititre EUMDROXF microplates is an alternative to the reference BMD method. However, MIC values ± 1 dilution apart from the breakpoint (2 mg/L) should be controlled by BMD; whereas the use of MTS gradient strips is discouraged. Disc diffusion might be useful for screening, unfortunately many cefiderocol resistant strains are not detected."

Journal

CTPS1 Is a Novel Therapeutic Target in Multiple Myeloma That Synergizes with Inhibition of ATR, CHEK1 or WEE1 (ASH 2022) - "Combining CTPS1 inhibition by STP938 with inhibitors of different components of the DDR pathway demonstrated strong synergy, with consistent results observed when combining STP938 with inhibitors of either ATR (ceralasertib, VE-821), CHEK1 (rabusertib, SRA737) or WEE1 (adavosertib) (Figure B). The ability of the homologous CTPS2 enzyme to compensate for CTPS1 loss outside the hematopoietic system suggests that inhibition of CTPS1 will not be associated with significant non-hematological toxicity. Clinical evaluation of STP938 in lymphoid malignancies will start in Q3 this year."

Hematological Malignancies • Monoclonal Gammopathy • Multiple Myeloma • ANXA5 • CHEK2

Low-molecular-weight cyclin E deregulates DNA replication and damage repair to promote genomic instability in breast cancer. (PubMed, Oncogene) - "Targeting the ATR-CHK1-RAD51 pathway with ATR inhibitor (ceralasertib), CHK1 inhibitor (rabusertib), or RAD51 inhibitor (B02) significantly decreased the viability of LMW-E-overexpressing hMECs and breast cancer cells. Collectively, our findings delineate a novel role for LMW-E in tumorigenesis mediated by replication stress tolerance and genomic instability, providing novel therapeutic strategies for LMW-E-overexpressing breast cancers."

Journal • Breast Cancer • Oncology • Solid Tumor • RAD51

Antigiardial Activity of Foeniculum vulgare Hexane Extract and Some of Its Constituents. (PubMed, Plants (Basel)) - "This aldehyde was less toxic (IC 588.8 µg/mL) than positive control metronidazole (IC 83.5 µg/mL) against Vero cells. The above results could support the use of F. vulgare in Mexican traditional medicine."

Journal

Identifying targetable markers of resistance to dual TORC1/2 inhibition in endometrial cancer cell lines. (ASCO 2022) - "TAK228 (TORC1/2, IC50 4-20nM), AZD7762 (CHK1/2, IC50 15-160nM), LY2603618 (CHK1, IC50 260nM-7.5mM) and cediranib (VEGFR2, 800nM-1mM) all had significant cytotoxic effects as individual agents on multiple endometrial cell lines. RPPA identified changes in phosphorylated CHK1/2 and total VEGFR2 as being correlated to resistance to dual TORC1/2 inhibition with TAK228 in multiple endometrial cancer cell lines. While single agent activity of TORC1/2, CHK1/2 and VEGFR2 inhibitors showed varying activity, combinations of TAK228 with either cediranib or AZD7762 showed significant synergism in multiple cell lines. Clinical examination of these combinations agents may prove useful in recurrent endometrial cancer."

Preclinical • Endometrial Cancer • Oncology • Solid Tumor • CHEK1 • CHEK2

CHST11-mediated microenvironment events contribute to pulmonary fibrosis and cancer progression. (PubMed, FASEB J) - "By reversing the CHST11-IL6/IL1B-IRF8-CD80/CD86 mediated axis, we confirmed that VE821 and LY2603618 have the value of drug repurposing. Our study proves novel insight into how CHST11 contributes to cystic fibrosis and lung cancer by reprogramming the immune microenvironment."

Journal • Cystic Fibrosis • Fibrosis • Genetic Disorders • Idiopathic Pulmonary Fibrosis • Immune Modulation • Immunology • Inflammation • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pulmonary Disease • Respiratory Diseases • Solid Tumor • CD86 • IL1B • IL6 • IRF8

Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion. (PubMed, Cancer Biol Ther) - "We further demonstrate that activating CXCL3-ERK1/2 signaling might contribute to the enhanced migratory capabilities rather than the acquired drug resistance. Our findings indicate that repeated treatments with the rabusertib/olaparib combination result in increased drug resistance and a more aggressive cell phenotype than those with either single agent, providing new clues for future clinical anticancer tests of PARP1 and Chk1 inhibitor combinations."

Journal • Oncology • CXCL3

Pharmacologic tumor PD-L1 depletion reduces Chk2 content and sensitizes tumors to small molecule Chk1 DNA damage repair inhibitors (SITC 2021) - "In vitro tests of β-lactam antibiotics used 80 μM and the Chk1 inhibitors rabusertib and prexasertib were used at indicated concentrations. Cefepime is the prototype agent, but ceftazidime is structurally similar with significant activity, suggesting important structure activity relationships to explore. Pharmacologic tumor PD-L1 depletion could augment other standard of care approaches, including immunotherapy, and deserves further investigation."

Bladder Cancer • Genito-urinary Cancer • Melanoma • Oncology • Ovarian Cancer • Solid Tumor • Urothelial Cancer • CHEK1 • CHEK2 • PD-1 • PD-L1

Chk1 and the Host Cell DNA Damage Response as a Potential Antiviral Target in BK Polyomavirus Infection. (PubMed, Viruses) - "The role of Chk1, a protein kinase known to be involved in the replication stress-induced DDR, was examined by inhibition with the small molecule LY2603618 and by siRNA-mediated knockdown...Activation of mitotic pathways was associated with the reduction in BKPyV replication. Chk1 inhibitors that are found to be safe and effective in clinical trials for cancer should also be evaluated for antiviral activity against BKPyV."

Journal • Fibrosis • Immunology • Infectious Disease • Nephrology • Oncology • Transplantation • CHEK1

CHK1 inhibitor sensitizes resistant colorectal cancer stem cells to nortopsentin. (PubMed, iScience) - "Synergistic combination of NORA234 and CHK1 (rabusertib) targeting is synthetic lethal inducing death of both CD44v6-negative and CD44v6-positive CRC stem cell fractions, aside from Wnt pathway activity. These data could provide a rational basis to develop an effective strategy for the treatment of patients with CRC."

Cancer stem cells • Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD44 • CHEK1

Radiosensitization by Kinase Inhibition Revealed by Phosphoproteomic Analysis of Pancreatic Cancer Cells. (PubMed, Mol Cell Proteomics) - "Pharmacological inhibition of the kinases FAK by Defactinib and of CHEK1 by Rabusertib showed a statistically significant sensitization to radiation in radioresistant PDAC cells. Together, the presented data map a comprehensive molecular network of radiation-induced signaling, improves the understanding of radioresistance and provides avenues for developing radiotherapeutic strategies."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Topsentinol L Trisulfate, a Marine Natural Product That Targets Basal-like and Claudin-Low Breast Cancers. (PubMed, Mar Drugs) - "The importance of targeting AMPK and CHK1 in BL-CL cell lines was validated by treating a panel of breast cancer cell lines with known small molecule inhibitors of AMPK (dorsomorphin) and CHK1 (Ly2603618) and recording the increased effectiveness against BL-CL breast cancers as compared with luminal/HER2+ breast cancer. Finally, we generated a drug response gene-expression signature and projected it against a human tumor panel of 12 different cancer types to identify other cancer types sensitive to the compound. The TLT sensitivity gene-expression signature identified breast and bladder cancer as the most sensitive to TLT, while glioblastoma multiforme was the least sensitive."

Journal • Bladder Cancer • Breast Cancer • Genito-urinary Cancer • Glioblastoma • HER2 Breast Cancer • Oncology • Solid Tumor • Urothelial Cancer • AMPK • CHEK1 • HER-2

Pharmacologic screening identifies synthetic lethality interactions with Chk1 inhibitors in basal-like breast and ovarian cancer (AACR 2018) - "...Combination of DNA-damaging agents, like platinum compounds or gemcitabine, with the Chk1 inhibitors LY2603618 and SAR020106 had a synergistic effect, not observed when combined with agents targeting mitosis, like taxotere, eribulin or vinorelbine...Finally, we wanted to evaluate the antiproliferative effect when adding LY2603618 to olaparib in addition to a DNA-damaging agent...Interestingly, inhibition of Chk1 also reverted the effect of cisplatin in platinum-resistant cells. Our findings support the clinical development of Chk1 inhibitors in combination with DNA-damaging agents in basal-like and ovarian cancer."

Breast Cancer • Ovarian Cancer

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer. (PubMed, Int J Mol Sci) - "Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib...Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin."

Journal • Breast Cancer • Oncology • Solid Tumor • CHEK1

Effect of CHK1 Inhibition on CPX-351 Cytotoxicity in vitro and ex vivo. (PubMed, Sci Rep) - "CPX-351 is a liposomally encapsulated 5:1 molar ratio of cytarabine and daunorubicin that recently received regulatory approval for the treatment of therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes based on improved overall survival compared to standard cytarabine/daunorubicin therapy. Moreover, CHK1 knockdown or addition of a CHK1 inhibitor such as MK-8776, rabusertib or prexasertib enhances CPX-351-induced apoptosis in multiple TP53-null and TP53-wildtype AML cell lines. Likewise, CHK1 inhibition increases the antiproliferative effect of CPX-351 on primary AML specimens ex vivo, offering the possibility that CPX-351 may be well suited to combine with CHK1-targeted agents."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

The phosphorylation of CHK1 at Ser345 regulates the phenotypic switching of vascular smooth muscle cells both in vitro and in vivo. (PubMed, Atherosclerosis) - "Our data demonstrated that phosphorylation of CHK1 under DNA damage stress modulates VSMCs phenotypic switching. CHK1 inhibition may be a potential therapeutic strategy for intima hyperplasia treatment."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • CHEK1

Chest CT accuracy in diagnosing COVID-19 during the peak of the Italian epidemic: A retrospective correlation with RT-PCR testing and analysis of discordant cases. (PubMed, Eur J Radiol) - "In our experience, in a context of high pre-test probability, CT scan shows good sensitivity and a consistently higher specificity for the diagnosis of COVID-19 pneumonia than what reported by previous studies, especially when clinical and epidemiological features are taken into account."

Journal • Retrospective data • Infectious Disease • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases