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DRUG CLASS:

Chk1 inhibitor

1d
A novel risk model consisting of nine platelet-related gene signatures for predicting prognosis, immune features and drug sensitivity in glioma. (PubMed, Hereditas)
Nine platelet-related prognostic genes identified as prognostic signatures for glioma were closely associated with the TME and may aid in directing the clinical treatment and prognosis of gliomas.
Journal • Gene Signature
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KIF20A (Kinesin Family Member 20A) • SULF2 (Sulfatase 2)
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AZD-7762
5d
PF-477736 modulates vascular smooth muscle cells phenotypic transition through Chk1/p53/CD44 pathway. (PubMed, Tissue Cell)
Our findings show that PF-477736 exerts anti-vascular remodeling effect by inhibiting phenotypic transition through the Chk1/p53/CD44 pathway in VSMCs, providing novel therapeutic strategies for preventing and treating vascular remodeling.
Journal
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CD44 (CD44 Molecule) • CHEK1 (Checkpoint kinase 1) • VIM (Vimentin) • PCNA (Proliferating cell nuclear antigen)
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CD44 expression • VIM expression
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PF-00477736
11d
Ion channel modulator DPI-201-106 significantly enhances antitumor activity of DNA damage response inhibitors in glioblastoma. (PubMed, Neurooncol Adv)
Combination treatment of DPI-201-106 with the CHK1 inhibitor prexasertib or the PARP inhibitor niraparib demonstrated synergistic effects in multiple patient-derived glioblastoma cells both in vitro and in intracranial xenograft mouse models, extending survival of glioblastoma-bearing mice. DPI-201-106 enhances the efficacy of DDR inhibitors to reduce glioblastoma growth. As these drugs have already been clinically tested in humans, repurposing DPI-201-106 in novel combinatorial approaches will allow for rapid translation into the clinic.
Journal • PARP Biomarker
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ANXA5 (Annexin A5)
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Zejula (niraparib) • prexasertib (ACR-368)
11d
Low PPP2R2A expression promotes sensitivity to CHK1 inhibition in high-grade serous ovarian cancer. (PubMed, Theranostics)
Our study suggests that PPP2R2A-KD elevates c-Myc-induced RS via upregulation of replication initiation, rendering HGSOC cells reliant on CHK1 for survival, including those resistant to PARP inhibitors. Combined, these results identify PPP2R2A/PP2A B55α as a potential predictive biomarker for CHK1i sensitivity in HGSOC, as well as suggesting it as a therapeutic target to overcome PARP resistance.
Journal • PARP Biomarker
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MYC (V-myc avian myelocytomatosis viral oncogene homolog) • PPP2R2A (Protein Phosphatase 2, Regulatory Subunit B, Alpha)
23d
Pharmacoinformatics-based prediction of Checkpoint kinase-1 inhibitors from Momordica charantia Linn. for cancer. (PubMed, Comput Biol Chem)
Among 86 compounds identified from M. charantia L., five molecules such as α-spinasterol (-9.7 kcal × mol-1), stigmasterol (-9.6 kcal × mol-1), stigmasta-7,22,25-trienol (-9.5 kcal × mol-1), campesterol (-9.5 kcal × mol-1), and stigmasta-7,25-dien-3beta-ol (-9.5 kcal × mol-1) and standard drug CCT245737 (-8.3 kcal × mol-1) displayed highest binding affinity with Chk-1...The estimation of binding free-energy derived from molecular docking was fully recognized by the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) produced from the MD simulation paths. Altogether, these five compounds may serve as effective inhibitors of Chk-1, thereby could be used to develop new medications for cancer treatment.
Journal
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CHEK1 (Checkpoint kinase 1)
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SRA737
1m
Inhibition of Chk1 with Prexasertib Enhances the Anticancer Activity of Ciclopirox in Non-Small Cell Lung Cancer Cells. (PubMed, Cells)
This was associated with increased expression of DR4, DR5, Fas, and FADD and decreased expression of survivin, resulting in activation of caspase 8 and caspase 3 as well as cleavage of poly (ADP ribose) polymerase (PARP). Taken together, the results suggest that inhibition of Chk1 with PRE can enhance the anticancer activity of CPX at least partly by decreasing cell proliferation and increasing apoptosis in NSCLC cells.
Journal • PARP Biomarker
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CDK4 (Cyclin-dependent kinase 4) • BIRC5 (Baculoviral IAP repeat containing 5) • CDK6 (Cyclin-dependent kinase 6) • CHEK1 (Checkpoint kinase 1) • FADD (Fas associated via death domain) • CASP3 (Caspase 3) • CASP8 (Caspase 8) • CDK2 (Cyclin-dependent kinase 2) • CDC25C (Cell Division Cycle 25C) • CDC25B (Cell Division Cycle 25B) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)
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BIRC5 expression
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prexasertib (ACR-368)
2ms
A Study of PEP07 (Checkpoint Kinase 1 Inhibitor) in Patients with Advanced or Metastatic Solid Tumors (clinicaltrials.gov)
P1, N=54, Recruiting, PharmaEngine | Not yet recruiting --> Recruiting | Trial completion date: Dec 2026 --> Aug 2027 | Trial primary completion date: Jul 2026 --> Feb 2027
Enrollment open • Trial completion date • Trial primary completion date • Metastases
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PEP07
2ms
Tumour-intrinsic PDL1 signals regulate the Chk2 DNA damage response in cancer cells and mediate resistance to Chk1 inhibitors. (PubMed, Mol Cancer)
Our data challenge the prevailing surface PDL1 paradigm, elucidate important and previously unappreciated roles for tumour-intrinsic PDL1 in regulating the ATM/Chk2 DNA damage response axis and E3 ligase-mediated protein degradation, suggest tumour PDL1 as a biomarker for Chk1i efficacy, and support the rapid clinical potential of pharmacologic tumour PDL1 depletion to treat selected cancers.
Journal • PD(L)-1 Biomarker • IO biomarker
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CHEK2 (Checkpoint kinase 2)
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PD-L1 expression
3ms
A Study of the Drugs Prexasertib, Irinotecan, and Temozolomide in People With Desmoplastic Small Round Cell Tumor and Rhabdomyosarcoma (clinicaltrials.gov)
P1/2, N=21, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025
Trial completion date • Trial primary completion date • Combination therapy
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temozolomide • irinotecan • prexasertib (ACR-368)
3ms
A Phase 1/2 Study of SMP-3124LP in Adults with Advanced Solid Tumors (clinicaltrials.gov)
P1/2, N=120, Recruiting, Sumitomo Pharma America, Inc. | Not yet recruiting --> Recruiting
Enrollment open • Metastases
3ms
Trial completion date • Combination therapy
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gemcitabine • cyclophosphamide • prexasertib (ACR-368) • Neulasta (pegfilgrastim) • Neupogen (filgrastim)
3ms
A Phase II Study of ACR-368 and Low Dose Gemcitabine in R/M HNSCC (clinicaltrials.gov)
P2, N=43, Recruiting, H. Lee Moffitt Cancer Center and Research Institute
New P2 trial • Combination therapy • Metastases
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gemcitabine • prexasertib (ACR-368)
4ms
Development of a Novel CD8+ T Cell-Associated Signature for Prognostic Assessment in Hepatocellular Carcinoma. (PubMed, Cancer Control)
The CD8+ T-cell-associated signature is expected to be a tool for optimizing individual patient decision-making and monitoring protocols, and to provide new ideas for treatment and prognostic assessment of HCC.
Retrospective data • Journal • IO biomarker
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CD8 (cluster of differentiation 8) • IL7R (Interleukin 7 Receptor) • CD7 (CD7 Molecule) • GZMH (Granzyme H) • FABP5 (Fatty Acid Binding Protein 5) • KLRB1 (Killer Cell Lectin Like Receptor B1) • RGS2 (Regulator Of G Protein Signaling 2)
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AZD-7762
5ms
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
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HMGB1 (High Mobility Group Box 1)
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berzosertib (M6620) • MK-8776
5ms
A Phase 1/2 Study of SMP-3124LP in Adults With Advanced Solid Tumors (clinicaltrials.gov)
P1/2, N=120, Not yet recruiting, Sumitomo Pharma America, Inc.
New P1/2 trial • Metastases
5ms
Gynecologic Cancer InterGroup CA125 response has a high negative predictive value for CHK1 inhibitor RECIST response in recurrent ovarian cancer. (PubMed, Sci Rep)
We investigated the association of CA125 response with prognosis and RECIST response/progressive disease (PD) criteria in recurrent high grade serous ovarian cancer (HGSOC) patients treated with a cell cycle checkpoint kinase 1 inhibitor (CHK1i), prexasertib...CA125 PD criteria also showed poor concordance with RECIST PD (PPV 56%, 95% CI: 40-71; NPV 33%, 95% CI: 17-54). Therefore, serum CA125 may be useful as a highly accessible prognostic and predictive biomarker to CHK1i therapy in recurrent HGSOC.
Journal • BRCA Biomarker • PARP Biomarker
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BRCA (Breast cancer early onset) • MUC16 (Mucin 16, Cell Surface Associated) • CHEK1 (Checkpoint kinase 1)
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prexasertib (ACR-368)
5ms
A phase II study of ACR-368 in patients with ovarian (OvCa) or endometrial carcinoma (EnCa) and prospective validation of OncoSignature patient selection (NCT05548296) (ESMO 2024)
BM-negative pts (Arm 2) received ACR-368 at RP2D with ultra-low dose of gemcitabine (ULDG; 10 mg/m2). Initial clinical data from this prospective trial supports the clinical utility of the ACR-368-OncoSignature as a pts selection tool to identify OvCa and EnCa pts sensitive to ACR-368.
P2 data • Clinical
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OncoSignature® Test
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gemcitabine • prexasertib (ACR-368)
5ms
CHK1 inhibitor SRA737 is active in PARP inhibitor resistant and CCNE1 amplified ovarian cancer. (PubMed, iScience)
SRA737 monotherapy in vivo prolonged survival in CCNE1 amp models, suggesting a potential biomarker for CHK1i therapy. Combination SRA737 and PARPi therapy increased tumor regression in both PARPi-resistant and CCNE1 amp patient-derived xenograft models, warranting further study in these HGSOC subgroups.
Journal • BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CCNE1 (Cyclin E1)
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SRA737
5ms
A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity. (PubMed, iScience)
Three compounds, N-acetyl-N-acetoxy chlorobenzenesulfonamide (NANAC), A-443654, and CHIR-124, were validated to reduce BRCA1 protein levels and sensitize breast cancer cells to the toxic effects of olaparib. These results suggest that BRCA1-HiBiT reporter cells hold promise in developing agents to improve the clinical utility of PARPi.
Journal • BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset)
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Lynparza (olaparib) • CHIR-124 • A 443654
6ms
Developing targeted therapies for neuroblastoma by dissecting the effects of metabolic reprogramming on tumor microenvironments and progression. (PubMed, Theranostics)
AZD7762 and etoposide were identified as potent therapeutics against MPS-I and II NB, respectively. This study provides deep insights into the molecular mechanisms underlying metabolic reprogramming-mediated malignant progression of NB. It also sheds light on developing targeted medications guided by the novel precise risk prognostication approaches, which could contribute to a significantly improved therapeutic strategy for NB.
Journal
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MYCN (MYCN Proto-Oncogene BHLH Transcription Factor)
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etoposide IV • AZD-7762
6ms
A Study of PEP07 (Checkpoint Kinase 1 Inhibitor) in Patients With Advanced Cancer (clinicaltrials.gov)
P1, N=32, Recruiting, PharmaEngine | Phase classification: P1b --> P1
Phase classification • Metastases
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PEP07
7ms
Mis-splicing of mitotic regulators sensitizes SF3B1-mutated human HSCs to CHK1 inhibition. (PubMed, Blood Cancer Discov)
Clinical CHK1i prexasertib selectively targeted SF3B1-mutant HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition.
Journal
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SF3B1 (Splicing Factor 3b Subunit 1) • CD34 (CD34 molecule) • BUB1B (BUB1 Mitotic Checkpoint Serine/Threonine Kinase B) • CDC27 (Cell Division Cycle 27)
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prexasertib (ACR-368)
7ms
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
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AR (Androgen receptor)
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Xtandi (enzalutamide) • MK-8776
7ms
The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity. (PubMed, Nat Commun)
Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity.
Journal
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RRM1 (Ribonucleotide Reductase Catalytic Subunit M1)
8ms
Construction of a Novel MitochondriaAssociated Gene Model for Assessing ESCC Immune Microenvironment and Predicting Survival. (PubMed, J Microbiol Biotechnol)
AZD1332 and AZD7762 were more effective for patients in the low-risk group, whereas Entinostat, Nilotinib, Ruxolutinib, and Wnt.c59 were more effective for patients in the high-risk group. Knockdown of TYMS significantly inhibited the proliferation and invasive ability of ESCC cells in vitro. Overall, our MAR model provides stable and reliable results and may be used as a prognostic biomarker for personalized treatment of patients with ESCC.
Journal
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TYMS (Thymidylate Synthetase)
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Tasigna (nilotinib) • Jingzhuda (entinostat) • AZD-7762
9ms
The CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial. (PubMed, Nat Commun)
Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.
P2 data • Journal • BRCA Biomarker
|
BRCA (Breast cancer early onset) • POLA1 (DNA Polymerase Alpha 1)
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BRCA wild-type
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prexasertib (ACR-368)
9ms
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.
Journal • IO biomarker
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RRM2 (Ribonucleotide Reductase Regulatory Subunit M2)
|
carmustine • AZD8055 • MK-8776
9ms
A Study of LY2880070 in Participants With Advanced or Metastatic Cancer (clinicaltrials.gov)
P1/2, N=229, Recruiting, Esperas Pharma Inc. | Phase classification: P1b/2a --> P1/2
Phase classification • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • PGR (Progesterone receptor)
|
HER-2 negative • ER expression
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gemcitabine • ESP-01
9ms
Trial completion date • Combination therapy
|
gemcitabine • cyclophosphamide • prexasertib (ACR-368) • Neulasta (pegfilgrastim) • Neupogen (filgrastim)
9ms
A Study of LY2880070 and Gemcitabine in People With Ewing Sarcoma,Ewing-Like Sarcoma, and Desmoplastic Small Round Cell Tumor (clinicaltrials.gov)
P2, N=24, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Mar 2024 --> Mar 2025 | Trial primary completion date: Mar 2024 --> Mar 2025
Trial completion date • Trial primary completion date • Combination therapy
|
WT1 (WT1 Transcription Factor) • BCOR (BCL6 Corepressor) • EWSR1 (EWS RNA Binding Protein 1) • ETV1 (ETS Variant Transcription Factor 1) • FLI1 (Fli-1 Proto-Oncogene ETS Transcription Factor) • ETV4 (ETS Variant Transcription Factor 4)
|
EWSR1-WT1 fusion
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gemcitabine • ESP-01
10ms
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
|
CHEK1 (Checkpoint kinase 1)
|
cisplatin • MK-8776
10ms
Acrivon predictive precision proteomics (AP3) uncovers mechanism of resistance to ACR-368, a clinical-stage CHK1/2 inhibitor, and identifies rational combination treatment (AACR 2024)
Here, we demonstrate the utility of AP3 for the identification of a key druggable resistance mechanism to ACR-368 and how to overcome that with low dose gemcitabine (gem), providing OncoSignature negative patients with a new potential therapeutic option. These data supported a dose escalation Phase 1b/2 clinical study of low dose gem with ACR-368 to evaluate the efficacy and safety of the combination in ACR-368 OncoSignature negative patients (NCT05548296). This shows the potential of AP3 for unbiased elucidation of actionable drug resistance mechanisms and rapid clinical implementation in our trials, which have recently confirmed clinical activity.
Clinical
|
OncoSignature® Test
|
gemcitabine • prexasertib (ACR-368)
10ms
POTENTIATE: Study of the CHK1 Inhibitor BBI-355, an ecDNA-directed Therapy (ecDTx), in Subjects With Tumors With Oncogene Amplifications (clinicaltrials.gov)
P1, N=150, Recruiting, Boundless Bio | Phase classification: P1/2 --> P1 | N=47 --> 150 | Trial completion date: Jan 2026 --> Sep 2027 | Trial primary completion date: Jan 2025 --> Sep 2026
Phase classification • Enrollment change • Trial completion date • Trial primary completion date • Combination therapy • Metastases
|
erlotinib • Lytgobi (futibatinib)
11ms
Actin filament-associated protein 1-antisense RNA1 promotes the development and invasion of tongue squamous cell carcinoma via the AFAP1-AS1/miR-133a-5p/ZIC2 axis. (PubMed, J Gene Med)
The upregulation of lncRNA AFAP1-AS1, which increases TSCC cell viability, migration, proliferation and invasion via the AFAP1-AS1/miR-133a-5p/ZIC2 axis, aids in the progression of TSCC.
Journal
|
AFAP1-AS1 (AFAP1 Antisense RNA 1) • ZIC2 (Zic Family Member 2)
|
AFAP1-AS1 overexpression
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docetaxel • Tasigna (nilotinib) • fexagratinib (ABSK091) • AZD-7762
11ms
Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer. (PubMed, Oncogene)
Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.
Journal • Synthetic lethality
|
WEE1 (WEE1 G2 Checkpoint Kinase)
|
adavosertib (AZD1775) • SRA737
11ms
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
|
PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CHEK1 (Checkpoint kinase 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
PIK3CA mutation
|
Piqray (alpelisib) • MK-8776
12ms
Investigations of the novel checkpoint kinase 1 inhibitor SRA737 in non-small cell lung cancer and colorectal cancer cells of differing tumour protein 53 gene status. (PubMed, Explor Target Antitumor Ther)
Also, greater anti-proliferative and cell killing effects were noted in the TP53 MUT cells than in the TP53 WT cells. This study's data suggests that P53 status/functioning is a key factor in determining the sensitivity of NSCLC and CRC cancer cells towards CHK1 inhibition, even in circumstances conducive to high replicative stress.
Journal
|
CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
|
TP53 mutation • TP53 wild-type
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SRA737
1year
Acrivon Therapeutics Announces FDA has Granted Breakthrough Device Designation for ACR-368 OncoSignature Assay for Ovarian Cancer (GlobeNewswire)
"Acrivon Therapeutics, Inc...announced the U.S. Food and Drug Administration (FDA) has granted Breakthrough Device designation for the ACR-368 OncoSignature assay, a multiplex immunofluorescence assay for the identification of ovarian cancer patients who may benefit from ACR-368 treatment. The designation reflects FDA’s determination that the device is reasonably expected to provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions."
FDA event
|
OncoSignature® Test
|
prexasertib (ACR-368)
1year
A Study of ACR-368 in Ovarian Carcinoma, Endometrial Adenocarcinoma, and Urothelial Carcinoma (clinicaltrials.gov)
P1/2, N=390, Recruiting, Acrivon Therapeutics | Phase classification: P1b/2 --> P1/2
Phase classification • Combination therapy • Pan tumor
|
gemcitabine • prexasertib (ACR-368)