rabusertib (LY 2603618)

PROTAC MA203 contains the type I kinase inhibitor rabusertib, which preferentially inhibits activated CHK1, and the cereblon (CRBN) ligand pomalidomide. Genetic CHK1 elimination confirms that such newly recognized functions of CHK1 rely on functions beyond its well-known catalytic activity. Thus, kinase-independent functions of CHK1 can be exploited with innovative pharmacological agents.

Moreover, the specific Chk1 inhibitor rabusertib (LY2603618) significantly enhanced the efficacy of doxorubicin in both ER+ and ER- cell lines. In summary, we have identified the association of a specific miRNA profile with highly proliferative luminal BCs and demonstrated the ability of hsa-miR-195-5p to inhibit CHEK1 expression in BC in vitro, underlining the importance of CHEK1 expression and its inhibition for prognosis and treatment of patients with luminal BCs.

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.

Proactive TDM and early dose optimization with vedolizumab may improve drug durability and clinical outcomes in pediatric patients with IBD.

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.

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.

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.

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.

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.