While targeted agents-such as LSD1 inhibitors, the BCL-2 inhibitor venetoclax, and IDH1 inhibitors-have provided clinical benefit, their efficacy is often limited by compensatory signaling and clonal evolution. This computational study supports the feasibility of a polypharmacology-based strategy for AML therapy by integrating epigenetic modulation, apoptotic reactivation, and metabolic correction within single molecular scaffolds. However, the identified compounds (Belumosudil, DB08512, and Elraglusib) have not yet demonstrated efficacy in AML models; further preclinical validation is warranted to substantiate these predictions and advance translational development.

P=N/A, N=0, Available, AMO Pharma Limited

As a result, these molecular events induced apoptosis and cell cycle arrest. In conclusion, our findings indicated that the selected compound 7f served as a highly promising lead compound, and this comprehensive approach demonstrated significant potential for the development of next-generation covalent GSK-3β inhibitors, which are expected to exhibit an improved therapeutic index and provide a more efficacious strategy for cancer therapy.

P1, N=40, Terminated, Actuate Therapeutics Inc. | N=68 --> 40 | Trial completion date: Dec 2024 --> Jul 2025 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Jul 2025; The decision to conclude study was made to optimize the clinical study design and protocol to further evaluate the safety profile of elraglusib (9-ING-41) in pediatric and adult patients with refractory Ewings Sarcoma.

Moreover, GSK‑3β knockdown inhibited sphere formation and invasion capacity, indicating that AZD1080 exerts inhibitory roles in a GSK‑3β‑dependent manner. Taken together, the results showed AZD1080 as a specific inhibitor of CSC stemness, without cytotoxicity, and indicated it was a promising therapeutic agent that targeted GSK‑3β signaling in osteosarcoma.

P2/3, N=76, Recruiting, AMO Pharma Limited | Trial completion date: Mar 2025 --> Dec 2026 | Trial primary completion date: Mar 2025 --> Dec 2026

P2, N=120, Recruiting, Hamilton Health Sciences Corporation | Not yet recruiting --> Recruiting | Trial completion date: Jul 2026 --> Jul 2027 | Trial primary completion date: Feb 2026 --> Feb 2027

However, varying concerns are reported throughout the literature including the risk of paradoxical arrhythmias, cancer and off-target effects in upstream or downstream pathways. CLINICAL RELEVANCE: In light of the start of the phase 2 TaRGET clinical trial, designed to evaluate the potential therapeutic efficacy of GSK3β inhibition in patients with arrhythmogenic cardiomyopathy, this report aims to review the advantages and disadvantages of this strategy.

Finally, in co-culture experiments with CD8 + T cells, 9-ING-41 improved immune recognition of the neuroblastoma cells, as evidenced by augmented T-cell activation marker levels and T-cell proliferation, which was further enhanced by PD-1 immune checkpoint inhibition. Our preclinical study provides experimental support to further explore the GSK-3β inhibitor 9-ING-41 as an immunomodulatory agent to increase tumor immune recognition in neuroblastoma.

GSK-3β functions as an oncogene in ATL and could be a potential therapeutic target.

P2, N=120, Not yet recruiting, Hamilton Health Sciences Corporation | Initiation date: Apr 2024 --> Oct 2024

In silico docking of the benzimidazole-oxindole hybrid 8v into the catalytic pocket of both CDK2 and GSK-3β revealed its perfect fitting through the formation of hydrogen bonding and hydrophobic interactions with the key amino acids in the binding sites. In addition, in silico absorption, distribution, metabolism, excretion studies proved that 8a-x exhibit satisfactory drug-likeness properties for drug development.