SRA737

Correspondingly, a higher sensitivity to SRA737 was observed in a docetaxel-resistant CRPC cell line with elevated KDM5D, and silencing KDM5D caused resistance to this inhibitor. SIGNIFICANCE STATEMENT: This study demonstrated an important role of an epigenetic regulator KDM5D in regulating CHK1 inhibitor sensitivity via a p38/COX-2-mediated prosurvival pathway in certain castration- or drug-resistant PC cells. Our results indicate that PC cells expressing KDM5D may be more sensitive to targeted inhibition of CHK1 kinase, highlighting the potential predictive value of this gene for CHK1-targeted therapies in PC.

Cardiomyocyte CHK1 S280 phosphorylation is a key step in angiotensin II-induced cardiac remodelling, through activation of the JAK1-STAT3 pathway. Pharmacological inhibition of CHK1 could be a potential therapeutic strategy for hypertensive heart failure.

SRA737 + LDHU upregulates pro-inflammatory chemokine expression through an ATM-NF-κB-dependent mechanism.

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.

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.

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.

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.

An e-pharmacophore model was developed based on the three-dimensional crystal structure of the CHK1 protein in complex with CCT245737. Thus, we propose the combined application of cisplatin and procaterol as a novel potential therapeutic strategy against human gastric cancer. The findings also highlight the relevance of CHK1 kinase as a drug target for enhancing the sensitivity of cytotoxic agents in cancer.

SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy.

Using an autochthonous adenocarcinoma mouse prostate (TRAMP) model that gives rise to NEPC tumors, we assessed the efficacy of AZD1775 and a highly selective Chk1 inhibitor SRA737 as single agents and in combination on the progression, survival, and metastatic spread of NEPC tumors in vivo. Mechanistically, the combination of Chk1 and Wee1 inhibitors synergized to reduce the inhibitory phosphorylation of CDK1 at Y15 and Cdc25c at S216, resulting in enhanced activation of CDK1/cyclin B complex, abrogation of G2/M checkpoint, and consequent premature mitotic entry, which ultimately led to mitotic catastrophe and apoptosis. Our findings provide promising preclinical evidence supporting the therapeutic values of Wee1 and Chk1 inhibitors as single agents and in combination for the treatment of NEPC.