- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Targeting CTPS1 and nucleotide biosynthesis pathways as a novel therapeutic approach in MYC-amplified medulloblastoma (Section 43) - Mar 5, 2024 - Abstract #AACR2024AACR_6536;
Previously, the CHK1 inhibitor, prexasertib, demonstrated robust brain accumulation and targeting of G3 MB in pre-clinical models...We further demonstrated robust synergy of CHK1 inhibition with either glutamine antagonists or other inhibitors of the de novo pyrimidine synthesis pathway, prolonging in vivo survival in an orthotopic xenograft G3 MB model. The results of this investigation confirm CTPS1 as a novel target in G3 MB, pinpoint a dependency on de novo pyrimidine rather than purine biosynthesis, and identifies a novel rational combination for treatment in MYC-amplified MB patients.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Combination of a chk1/2 dual inhibitor (prexasertib) and gemcitabine reveals a novel intrinsic synergy mechanism in head and neck squamous cell carcinoma (Section 29) - Mar 5, 2024 - Abstract #AACR2024AACR_5416;
Cell cycle analysis revealed a replication catastrophe and increased pH2AX across multiple HNSCC cell lines following combination treatment.Our findings highlight the significance of CHK1/2 inhibition coupled with nucleoside analog-induced DNA damage in unveiling novel intrinsic signaling mechanisms in HNSCC. These insights offer a promising avenue for targeted therapeutic strategies to enhance treatment efficacy and outcomes in HNSCC.This work has been supported by the MGC, FC, P&MC, and BBSR at the H. Lee Moffitt Cancer Center & Research Institute, a comprehensive cancer center designated by the National Cancer Institute (P30-CA076292).
- |||||||||| Zepzelca (lurbinectedin) / PharmaMar, Jazz
Chk1/2 inhibition enhances response to lurbinectedin treatment in small cell lung cancer (Section 23) - Mar 5, 2024 - Abstract #AACR2024AACR_5325;
Western blot analysis of intracellular proteins from the same SCLC cell lines treated with both drugs demonstrate dose-dependent effects on cell death marker cPARP, DNA damage marker ?H2AX, and DDR/cell cycle pathway kinases cdk1 and 2. Ongoing experiments seek to replicate results using alternative Chk1/2 inhibitors, and to explore the effect of lurbinectedin-Chk1/2 inhibitor combination treatment on antitumor immune effector function by in vitro co-culture.
- |||||||||| nitazoxanide / Generic mfg.
Journal: Transcriptional Differential Analysis of Nitazoxanide-Mediated Anticanine Parvovirus Effect in F81 Cells. (Pubmed Central) - Feb 28, 2024
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.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Phase classification, Combination therapy, Monotherapy, Pan tumor: A Study of ACR-368 in Ovarian Carcinoma, Endometrial Adenocarcinoma, and Urothelial Carcinoma (clinicaltrials.gov) - Nov 13, 2023
P1/2, N=390, Recruiting,
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. Phase classification: P1b/2 --> P1/2
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Mitotic Dysregulation Sensitizes Malignant Stem Cells to CHK1 Inhibition in SF3B1-Mutant Myeloid Neoplasms (Marriott Marquis - Pacific Ballroom) - Nov 3, 2023 - Abstract #ASH2023ASH_1362;
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.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
P2 data, Journal, BRCA Biomarker, PARP Biomarker: A Phase 2 study of prexasertib (LY2606368) in platinum resistant or refractory recurrent ovarian cancer. (Pubmed Central) - Oct 22, 2023
P2
Prexasertib demonstrated durable single agent activity in a subset of patients with recurrent ovarian cancer regardless of clinical characteristics, BRCA status, or prior therapies, including PARPi. There was no obvious correlation with genomic alterations in responders vs non-responders, emphasizing the need for alternative biomarker approaches for responder identification.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap, navitoclax (ABT 263) / AbbVie
Preclinical, Journal: Simultaneous inhibition of Chk1 and Bcl-xL induces apoptosis in (Pubmed Central) - Oct 22, 2023
Treatment to control volume ratios were calculated as 63.2% for prexasertib, 79.4% for navitoclax, and 36.8% for prexasertib and navitoclax. These findings suggest that the simultaneous inhibition of Chk1 and Bcl-xL may be an effective treatment for pancreatic cancer.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap, samotolisib (LY3023414) / Eli Lilly
Trial completion, Trial completion date, Metastases: ExIST: LY3023414 and Prexasertib in Metastatic Triple-negative Breast Cancer (clinicaltrials.gov) - Sep 11, 2023
P2, N=10, Completed,
Pharmacogenomics analysis showed three therapeutic agents (NVP-BEZ235, LY2606368, and rutin) Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Nov 2022
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Biomarker, Journal, BRCA Biomarker, PARP Biomarker: BLM overexpression as a predictive biomarker for CHK1 inhibitor response in PARP inhibitor-resistant BRCA-mutant ovarian cancer. (Pubmed Central) - Jun 25, 2023
P2
Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA-mutant HGSC cells and xenograft mouse models...BRCA reversion mutation in previously PARPi-treated BRCA-mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA-mutant HGSC.
- |||||||||| telaglenastat (CB-839) / Calithera, prexasertib (ACR-368) / Acrivon Therap
Glutaminase inhibition induces replication stress in ovarian cancer cells and inhibition of replication checkpoint causes synthetic lethality (Section 38; Poster Board #14) - Mar 14, 2023 - Abstract #AACR2023AACR_7078;
Furthermore, CB839 and Prexasertib combination was more synergistic in cells that expressed high GLS compared to low GLS-expressing OC cells indicating the specificity of the combination of these drugs. Together, our studies identified a novel connection between metabolic and DNA damage checkpoint pathways in OC and propose a novel synergistic lethality-based combination therapy to treat chemo-resistant and aggressive OC.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
PARG inhibition augments CHK1 inhibitor-induced replication stress and synergistically kills ovarian cancer cells (Section 14; Poster Board #3) - Mar 14, 2023 - Abstract #AACR2023AACR_4889;
Together, these results indicate that this combination treatment cause persistence of heavy PARylation at DNA damage sites abrogates cell cycle checkpoint mechanisms, exhausts cellular NAD+ levels, and inhibits DNA repair leading to the metabolic and mitotic collapse of cancer cells and synergistic lethality in OC cells. Currently, prexasertib is under clinical trials and our studies will provide novel mechanistic insight into the therapeutic potential of this combination and provides preclinical evidence to develop further this combination therapy in treating OC.
- |||||||||| XS-02 / XSXH Therap
Discovery of a novel and oral CHK1 inhibitor for the treatment of solid tumors (Section 17; Poster Board #13) - Mar 14, 2023 - Abstract #AACR2023AACR_2543;
Prexasertib (LY2606368), one of the few agents to undergo clinical trials, specifically inhibits both CHK1 and CHK2, displaying obvious therapeutic effects but also raising inevitable target-associated drug toxicities and a potential compliance issue due to intravenous administration...Moreover, the combination of XS-02 and olaparib, a PARP inhibitor, accelerated tumor regression, which synergy was confirmed in a patient-derived tumor xenograft animal model of acquired resistance to olaparib, without significant body weight changes...These results support the agent as a clinical candidate for the treatment of solid tumors. An Investigational New Drug application is planned for 2023.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap, MS023 / University of Montreal, McGill University
Clonal Trajectories and Therapeutic Targeting of High-Risk SF3B1-Mutant Myelodysplastic Syndromes (ENMCC - 260-262) - Nov 4, 2022 - Abstract #ASH2022ASH_1384;
By contrast, CHK1 inhibitor Prexasertib was highly selective for SF3B1-mutant cells irrespective of co-mutations, inhibiting growth and cell cycle progression...In conclusion, progression from low-risk SF3B1-mutant MDS to high-risk disease is mediated by molecularly distinct trajectories driven by RUNX1 and STAG2 mutations that converge on expansion of the HSC compartment. Moreover, clonal progression is associated with genotype-specific drug responses and increased resistance to standard agents, and ongoing studies are elucidating how genetic and epigenetic states affect therapeutic responses.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Trial completion date, Trial primary completion date, Combination therapy: A Study of the Drugs Prexasertib, Irinotecan, and Temozolomide in People With Desmoplastic Small Round Cell Tumor and Rhabdomyosarcoma (clinicaltrials.gov) - Oct 4, 2022
P1/2, N=21, Active, not recruiting,
Additionally, our study builds on the growing evidence that DNA damage repair and replication stress response pathways offer therapeutic vulnerabilities for the treatment of neuroblastoma. Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Sep 2022 --> Sep 2023
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Journal: Inhibition of Chk2 promotes neuroprotection, axon regeneration, and functional recovery after CNS injury. (Pubmed Central) - Sep 20, 2022
Inhibitors of ATM-Chk2, but not the parallel ATR-Chk1 pathway, also promote marked, functional recovery after acute central nervous system injury in rats, suggesting that inhibiting nonhomologous end-joining rather than homologous recombination is crucial for neuroprotection. We demonstrate that the Chk2 inhibitor, prexasertib, which has been evaluated in phase 2 clinical trials for cancer, has potent neuroprotective effects and represents a new treatment option to promote functional recovery after spinal cord or optic nerve injury.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Trial termination, Metastases: A Phase II Single Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation Associated Breast or Ovarian Cancer, Triple Negative Breast Cancer, High Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer (clinicaltrials.gov) - Sep 10, 2022
P2, N=111, Terminated,
We demonstrate that the Chk2 inhibitor, prexasertib, which has been evaluated in phase 2 clinical trials for cancer, has potent neuroprotective effects and represents a new treatment option to promote functional recovery after spinal cord or optic nerve injury. Completed --> Terminated; Eli Lilly prematurely terminated the study.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap, cofetuzumab pelidotin (ABBV-647) / Pfizer, AbbVie, GSK461364 / GSK
Journal: Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention. (Pubmed Central) - Aug 22, 2022
Furthermore, using high-throughput drug sensitivity testing (525 drugs) we show that targeting PTK7 exhibited synergistic activity with chemotherapeutic agent paclitaxel, CHK1/2 inhibitor prexasertib, and PLK1 inhibitor GSK461364, among others, in OC cells and ex vivo primary samples. Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap, samotolisib (LY3023414) / Eli Lilly
Trial completion date, Metastases: ExIST: LY3023414 and Prexasertib in Metastatic Triple-negative Breast Cancer (clinicaltrials.gov) - Jul 20, 2022
P2, N=10, Active, not recruiting,
Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer. Trial completion date: Aug 2022 --> Dec 2022
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma (Forum) - Jul 19, 2022 - Abstract #EANO2022EANO_163;
P1
To identify the best-in-class, multiple different CHK1/2 inhibitors were compared and indicated that LY2606368 (prexasertib) had the strongest chemosensitizing activity in MB leading to further clinical investigation in th SJ-ELIOT clinical trial (NCT04023669). Moreover, these data demonstrate that we have developed a robust and collaborative preclinical assessment platform that can be used to identify potentially effective new therapies to be taken forward to the clinic for pediatric MB.
- |||||||||| prexasertib (ACR-368) / Acrivon Therap
Trial completion, Trial completion date, Trial primary completion date, Combination therapy: Prexasertib (LY2606368), Cytarabine, and Fludarabine in Patients With Relapsed or Refractory Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome (clinicaltrials.gov) - Jul 13, 2022
P1, N=15, Completed,
Moreover, these data demonstrate that we have developed a robust and collaborative preclinical assessment platform that can be used to identify potentially effective new therapies to be taken forward to the clinic for pediatric MB. Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Jul 2022 | Trial primary completion date: Dec 2022 --> Jul 2022
- |||||||||| prexasertib (ACR-368) / Acrivon Therap, Xerava (eravacycline) / SOM Biotech, Ewha Womans University, La Jolla Pharma, PAION
Journal: A Study of Drug Repurposing to Identify SARS-CoV-2 Main Protease (3CLpro) Inhibitors. (Pubmed Central) - Jul 2, 2022
Among the three compounds, only eravacycline showed potential antiviral activities with no significant cytotoxicity. A further study is planned for pre-clinical trials.
- |||||||||| prexasertib (LY2606368) / Eli Lilly, SOM Biotech, Ewha Womans University
Journal: Combating CHK1 resistance in triple negative breast cancer: EGFR inhibition as potential combinational therapy. (Pubmed Central) - May 19, 2022
In the article by Lee et al., the authors identify that, while prexasertib (a CHK1 inhibitor) lacks efficacy alone, combination with an EGFR inhibitor provides synergistic anti-tumor effects. Advances in targeted therapy for TNBC will benefit the clinical landscape for this disease, with this study initiating a new avenue of investigation.
- |||||||||| PF-00477736 / Pfizer, prexasertib (LY2606368) / Eli Lilly, SOM Biotech, Ewha Womans University
Journal: Chk1 inhibition potently blocks STAT3 tyrosine705 phosphorylation, DNA binding activity, and activation of downstream targets in human multiple myeloma cells. (Pubmed Central) - Apr 28, 2022
Gene expression profiling of U266 cells exposed to low (nmol/L) Chk1 inhibitor [PF-477736 (PF)] concentrations revealed STAT3 pathway-related gene downregulation (e.g., BCL-XL, MCL-1, c-Myc), findings confirmed by RT-PCR...Similar findings were obtained in other multiple myeloma cells and with alternative Chk1 inhibitors (e.g., prexasertib, CEP3891)...PF also inactivated STAT3 in primary human CD138+ MM cells and tumors extracted from an NSG MM xenograft model while inhibiting tumor growth. Implications: These findings identify a heretofore unrecognized link between the Chk1 and STAT3 pathways and suggest that Chk1 pathway inhibitors warrant attention as novel and potent candidate STAT3 antagonists in myeloma.
- |||||||||| prexasertib (LY2606368) / Eli Lilly, SOM Biotech, Ewha Womans University
Journal: Salt-Inducible Kinase 1 is a potential therapeutic target in Desmoplastic Small Round Cell Tumor. (Pubmed Central) - Apr 22, 2022
Lastly, combined inhibition of SIK1 and CHEK1with small molecule inhibitors, YKL-05-099 and prexasertib, respectively, showed enhanced cytotoxicity in DSRCT cells compared to inhibition of either kinases alone. This work identified SIK1 as a new potential therapeutic target in DSRCT and the efficacy of SIK1 inhibition may be improved when combined with other intervention strategies.
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