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DRUG CLASS:

Chk2 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
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)
15d
A missense variant effect map for the human tumor-suppressor protein CHK2. (PubMed, Am J Hum Genet)
It also provides strong evidence toward pathogenicity for some clinical missense variants and supporting evidence toward benignity for others. Overall, this comprehensive missense variant effect map contributes to understanding of both known and yet-to-be-observed CHK2 variants.
Journal • BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset) • CHEK2 (Checkpoint kinase 2)
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)
1m
Guarding against digestive-system cancers: Unveiling the role of Chk2 as a potential therapeutic target. (PubMed, Genes Dis)
In addition, we summarize evidence indicating that Chk2 can serve as a novel therapeutic target, based on its contributions to radiochemotherapy-resistance reversion and progress made in developing antitumor agents against Chk2. The prevailing evidence supports the conclusion that further research on Chk2 will provide a deeper understanding of digestive-system tumorigenesis and should suggest novel therapeutic targets.
Review • Journal
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CHEK2 (Checkpoint kinase 2)
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
Trial completion date • Combination therapy
|
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)
3ms
CEP-1347 Boosts Chk2-Mediated p53 Activation by Ionizing Radiation to Inhibit the Growth of Malignant Brain Tumor Cells. (PubMed, Int J Mol Sci)
CEP-1347 promoted IR-induced Chk2 phosphorylation and increased p53 expression in concert with IR in a Chk2-dependent manner. The present results show, for the first time, that CEP-1347 is capable of promoting Chk2-mediated p53 activation by IR in addition to inhibiting the expression of MDM4 and, thus, CEP-1347 has potential as a radiosensitizer for malignant brain tumors expressing wild-type p53.
Journal • Tumor cell
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CHEK2 (Checkpoint kinase 2) • MDM4 (The mouse double minute 4)
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TP53 wild-type • TP53 expression
4ms
Correlation between Molecular Docking and the Stabilizing Interaction of HOMO-LUMO: Spirostans in CHK1 and CHK2, an In Silico Cancer Approach. (PubMed, Int J Mol Sci)
In addition, Highest Occupied Molecular Orbital-Lowest Unoccupied Molecular Orbital (HOMO-LUMO) interactions were analyzed to study the stability of interactions between the selected enzymes and spirostans resulting in the predominant gaps from HOMOCHKs to LUMOSp (Highest Occupied Molecular Orbital of CHKs-Lowest Unoccupied Molecular Orbital of spirostan). In brief, this study presents the selection inhibitors of CHK1 and CHK2 as a potential treatment for cancer using a combination of molecular docking and dynamics, ADMETx predictons, and HOMO-LUMO calculation for selection.
Journal
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CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
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
4ms
Metformin combined with cisplatin reduces anticancer activity via ATM/CHK2-dependent upregulation of Rad51 pathway in ovarian cancer. (PubMed, Neoplasia)
The standard first-line therapy for OC involves cytoreductive surgical debulking followed by chemotherapy based on platinum and paclitaxel. Using an ATM inhibitor, KU55933, effectively reversed the cisplatin resistance phenotype. In conclusion, our results suggest that met can antagonize the effects of cDDP in specific types of OC cells, leading to a reduction in the chemotherapeutic efficacy of cDDP.
Journal
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CHEK2 (Checkpoint kinase 2) • RAD51 (RAD51 Homolog A)
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cisplatin • paclitaxel • metformin • KU-55933
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
Citrinin Provoke DNA Damage and Cell-Cycle Arrest Related to Chk2 and FANCD2 Checkpoint Proteins in Hepatocellular and Adenocarcinoma Cell Lines. (PubMed, Toxins (Basel))
The CIT IC50 for HepG2 was 107.3 µM, and for A549, it was >250 µM. The results showed that sensitivity to CIT is cell-type dependent and that CIT in sub-IC50 and near IC50 induces significant DNA damage and cell-cycle arrest in the G2/M phase, which is related to the increase in total and phosphorylated Chk2 and FANCD2 checkpoint proteins in HepG2 and A549 cells.
Preclinical • Journal
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CHEK2 (Checkpoint kinase 2) • FANCD2 (FA Complementation Group D2)
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)
6ms
Alantolactone Induced Apoptosis and DNA Damage of Cervical Cancer through ATM/CHK2 Signaling Pathway. (PubMed, Biol Pharm Bull)
In vivo studies with a xenograft mouse model further validated ALT's effectiveness in reducing CC tumor growth and promoting apoptosis. This study offers new insights into how ALT combats CC, highlighting its promise as an effective anti-cervical cancer agent and providing hope for improved treatment outcomes for CC patients.
Journal
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CHEK2 (Checkpoint kinase 2)
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
Inhibition of Melanoma Cell Growth by Salvianolic Acid A through CHK2-CDC25A Pathway Modulation. (PubMed, Front Biosci (Landmark Ed))
Salvianolic acids, especially Sal A, effectively hinder melanoma cell growth by inducing Chk-2 phosphorylation and disrupting G2/M checkpoint regulation.
Journal
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CHEK2 (Checkpoint kinase 2) • CDC25C (Cell Division Cycle 25C) • CDK1 (Cyclin-dependent kinase 1) • CDC25A (Cell Division Cycle 25A) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)
6ms
The phosphorylation-deubiquitination positive feedback loop of the CHK2-USP7 axis stabilizes p53 under oxidative stress. (PubMed, Cell Rep)
Compared to peri-tumor tissues, thyroid cancer and colon cancer tissues show higher CHK2 and phosphorylated USP7 (S168, T231) levels, and these levels are positively correlated. Collectively, our results uncover a phosphorylation-deubiquitination positive feedback loop involving the CHK2-USP7 axis that supports the stabilization of p53 and the maintenance of cell homeostasis.
Journal
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CHEK2 (Checkpoint kinase 2) • USP7 (Ubiquitin Specific Peptidase 7)
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)
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
8ms
Chk2 Modulates Bmi1-Deficiency-Induced Renal Aging and Fibrosis via Oxidative Stress, DNA Damage, and p53/TGFβ1-Induced Epithelial-Mesenchymal Transition. (PubMed, Int J Biol Sci)
Our study reveals mechanisms whereby Bmi1 preserves renal structure and function during aging by suppressing DDR and p53/TGFβ1-mediated EMT. These pathways represent potential targets for detecting and attenuating age-related renal decline.
Journal
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TP53 (Tumor protein P53) • CHEK2 (Checkpoint kinase 2) • BMI1 (BMI1 proto-oncogene, polycomb ring finger) • TGFB1 (Transforming Growth Factor Beta 1)
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
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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
Trial completion date • Combination therapy
|
gemcitabine • cyclophosphamide • prexasertib (ACR-368) • Neulasta (pegfilgrastim) • Neupogen (filgrastim)
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
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OncoSignature® Test
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gemcitabine • prexasertib (ACR-368)
10ms
Relationship between the Expression of CHK2 and p53 in Tumor Tissue and the Course of Papillary Thyroid Cancer in Patients with CHEK2 Germline Mutations. (PubMed, Cancers (Basel))
Higher CHK2 expression was associated with poorer treatment responses and disease outcomes. Higher CHK2 expression and positive p53 together with a TP53 deletion could be a prognostic marker of unfavorable disease outcomes in patients with germline truncating mutations in CHEK2.
Journal
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TP53 (Tumor protein P53) • CHEK2 (Checkpoint kinase 2)
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TP53 mutation • TP53 deletion • CHEK2 mutation • TP53 expression
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
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AFAP1-AS1 (AFAP1 Antisense RNA 1) • ZIC2 (Zic Family Member 2)
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AFAP1-AS1 overexpression
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docetaxel • Tasigna (nilotinib) • fexagratinib (ABSK091) • AZD-7762
1year
In silico and structure-based evaluation of deleterious mutations identified in human Chk1, Chk2, and Wee1 protein kinase. (PubMed, J Cell Biochem)
Furthermore, 25 mutations in Chk1, 189 in Chk2, and 14 in Wee1 were highly conserved, possessing deleterious effect and also influencing the protein structure and function. These identified mutations may provide underlying genetic intricacies to serve as potential targets for therapeutic inventions and clinical management.
Journal
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CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1)
1year
Evaluation of Synergistic Anti-Leukemic Efficacy of PHI-101 in Preclinical Model of FLT3-ITD Acute Myeloid Leukemia (ASH 2023)
Study Design and Combination effects of simultaneous versus sequential treatment of PHI-101 with other agents, including daunorubicin, cytarabine, venetoclax (Ven), and azacytidine (Aza) were tested using human leukemia cell lines harboring FLT3-ITD mutations (MV4-11, Molm13, Molm14) or FLT3-wild type as controls...The GI 50 of the gilteritinib was 5... Treatment of AML cells with the combination of Ven or Aza with PHI-101 in vitro induced rapid induction of apoptosis and inhibition of cell growth that showed significant synergy. In vivo data showed improved efficacy for the combination treatment with these agents. In vitro and in vivo data from the preclinical AML models provides a rationale to evaluate the activity of PHI-101 in combination for patients who are ineligible for more intensive chemotherapeutic induction therapy.
Preclinical • PARP Biomarker • IO biomarker
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FLT3 (Fms-related tyrosine kinase 3) • BCL2 (B-cell CLL/lymphoma 2) • ANXA5 (Annexin A5)
|
FLT3-ITD mutation • FLT3 mutation • BCL2 expression • FLT3 wild-type
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Venclexta (venetoclax) • Xospata (gilteritinib) • azacitidine • daunorubicin • PHI-101
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
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OncoSignature® Test
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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
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gemcitabine • prexasertib (ACR-368)
1year
Mitotic Dysregulation Sensitizes Malignant Stem Cells to CHK1 Inhibition in SF3B1-Mutant Myeloid Neoplasms (ASH 2023)
In conclusion, we developed a precise gene editing strategy of human HSCs to identify prexasertib as a promising therapy for SF3B1m myeloid neoplasms, and implicate the mitotic function of CHK1 as a SF3B1m sensitivity. The safety and toxicity profiles displayed in early phase clinical trials make prexasertib a suitable agent for further clinical investigation in SF3B1m MDS and its advanced stages.
IO biomarker
|
RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • CD38 (CD38 Molecule) • CD34 (CD34 molecule) • STAG2 (Stromal Antigen 2) • BUB1B (BUB1 Mitotic Checkpoint Serine/Threonine Kinase B) • CDC27 (Cell Division Cycle 27)
|
RUNX1 mutation • SF3B1 mutation • SF3B1 K700E
|
prexasertib (ACR-368)
1year
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 2023 --> Sep 2024 | Trial primary completion date: Sep 2023 --> Sep 2024
Trial completion date • Trial primary completion date • Combination therapy
|
temozolomide • irinotecan • prexasertib (ACR-368)
1year
Immune perturbation network identifies an EMT subtype with chromosomal instability and tumor immune-desert microenvironment. (PubMed, iScience)
This subtype tended to metastasize and was resistant to respond to immunotherapy. Pharmacogenomics analysis showed three therapeutic agents (NVP-BEZ235, LY2606368, and rutin) were potential interventions for MNG-4.
Journal • Tumor mutational burden • IO biomarker
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TMB (Tumor Mutational Burden)
|
TMB-L
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dactolisib (RTB101) • prexasertib (ACR-368)
over1year
ExIST: LY3023414 and Prexasertib in Metastatic Triple-negative Breast Cancer (clinicaltrials.gov)
P2, N=10, Completed, Baylor Research Institute | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Nov 2022
Trial completion • Trial completion date • Metastases
|
ER (Estrogen receptor)
|
ER negative
|
prexasertib (ACR-368) • samotolisib (LY3023414)
over1year
Chk2 Inhibitor for Recurrent EpitheliAl periToneal, fallopIan or oVarian cancEr (CREATIVE Phase IA Trial) (clinicaltrials.gov)
P1, N=36, Recruiting, Seoul National University Hospital | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2023
Trial completion date • Trial primary completion date
|
HRD (Homologous Recombination Deficiency)
|
HRD
|
PHI-101