obatoclax (GX 15-070)

We discussed some interesting examples, like HSP90 inhibitors (ganetespib), HDAC inhibitors (quisinostat), topoisomerase inhibitors (doxorubicin), and BCL-2 family antagonists (Obatoclax, TW-37), whose therapeutic activities are tightly regulated by circadian control over their molecular targets, pharmacokinetic processes, and downstream physiological pathways. Furthermore, the circadian influence extends to the tumor microenvironment and antitumor immunity, suggesting novel chrono-immunotherapy approaches. By putting together the molecular bases of these temporal dynamics, this review underscores the significant potential of chronotherapythe timed administration of drugs to improve cancer treatment by enhancing therapeutic indices and paving the way for personalized, temporally optimized oncology strategies.

Under ER stress responses, GBM cells exerted an autophagy response to recover from the stress condition; however, obatoclax co-treatment disrupted the autophagy responses, particularly by disrupting autophagic cargo degradation. Our findings suggest that targeting Mcl-1 and Bcl-xL, coupled with ER-stress induction, could be a promising strategy for the treatment of GBM, highlighting the potential for combination therapies involving pan-Bcl-2 family inhibitors to overcome current limitations in the treatment of GBM.

Based on these results, butylcycloheptyl prodigiosin and prodigiosin-R2 could be more effective BH3 mimetics and should be further studied.

In the in silico studies, molecular docking of two ligands, Ursolic acid and Obatoclax, with the Bcl-B protein demonstrated notable binding affinities, with ΔG values of -5.8 kcal/mol and - 6.6 kcal/mol, respectively...Further, BIOWIN™ models indicated that the identified Ursolic Acid is biodegradable in an aerobic environment, underscoring its environmental compatibility. Deciphering the bioactivities of ursolic acid could uncover new therapeutic agents and enhance our understanding of its biodegradable environmental compatibility, revealing the source of already documented pharmacological compounds.

Therapeutic strategies targeting Bcl‑2 (for example inhibitors such as venetoclax, navitoclax, obatoclax and combination therapies involving autophagy modulators) were evaluated for their potential efficacy. Future research should prioritize these areas and leverage advanced single‑cell technologies to elucidate the real‑time dynamics of Bcl‑2 in cell processes. The present review highlights the key role of Bcl‑2 in cell fate determination and highlights its potential as a therapeutic target, offering insight for the development of innovative treatments for cancer, neurodegenerative disorder and age‑related diseases.

Our study presents novel insights into the relationship between the Bcl-2 family and cisplatin efficacy in OSCC. It also demonstrates that targeted therapy with BH-3 mimetics, such as obatoclax, may represent a new strategy for OSCC therapy.

Docking analysis indicated a strong affinity of zeaxanthin to BCL-2 (ΔG = -9.773241 kcal/mol) compared to obatoclax (ΔG = -7.419345 kcal/mol)...EGY7 carotenoids are a promising anticancer agent against MDA-MB-231 cells. They effectively promote apoptosis and prevent metastasis, crucial for disease advancement in cancer cells.

The results demonstrated that the selected and prioritized phytochemicals, Withanolide L, Withanolide M, and Withanolide A display comparable efficacy to Obatoclax (CID: 11404337) and other known synthetic, semi-synthetic, and natural inhibitors of Bcl-2 family proteins. These findings establish a strong bench foundation for further experimental validation and bedside application, potentially offering an alternative natural approach to cancer therapy.

The identified molecules also exhibited specific interactions with critical amino acid residues of the binding cleft, highlighting their potential as lead candidates. Finally, molecular dynamics simulations and MM/PBSA based binding free energy analysis revealed that Enterolactone (CID_114739) and Piperine (CID_638024) molecules were on par with Obatoclax (CID_11404337), which is a known inhibitor of the Bcl-2 family proteins.Communicated by Ramaswamy H. Sarma.

We found that bcl-2 inhibitor (Obatoclax Mesylate) and TKI (Gefitinib) may have less sensitivity in our high-risk group ( P<0. 05), while some unconventional drugs (paclitaxe, dactinomycin, camptothecin, irinotecan and vinorelbine) may benefit in patients with higher FRGs expression (Figure J). In summary, we identified and validated 10 FRGs signature to well predict the prognosis and drug sensitivity of AML. Based on our findings, appropriate combination of new drugs at the time of treatment may achieve unexpected therapeutic outcomes, but still need to go through further verification.

The highest synergies were observed in the drug combinations Lapatinib with Thapsigargin and Lapatinib with Obatoclax Mesylate, both targeting epidermal growth factor receptor and affecting the apoptosis pathway. To further elaborate on the apoptosis cascade, we investigated other, more clinically relevant, apoptosis inducers and observed a strong synergistic effect while combining Venetoclax (BCL targeting) and AZD5991 (MCL1 targeting). Overall, we have identified via a high-throughput drug screening several new treatment strategies for GBM. Moreover, an exceptionally strong synergistic interaction was discovered between kinase targeting and apoptosis induction which is suitable for further clinical evaluation as multi-targeted combination therapy.