GSK 1838705A / GSK - LARVOL DELTA

Prevention of Protease-Induced Degradation of Desmoplakin via Small Molecule Binding. (PubMed, J Pers Med) - "We find that several molecules, including sodium dodecyl sulfate, palmitoylethanolamide, GW0742, salirasib, eprosarten mesylate, and GSK1838705A prevent wildtype and disease-variant-carrying DSP protein degradation in the presence of both trypsin and calpain without altering protease function. Molecular dynamic simulations of DSP-drug complexes suggest that some long hydrophobic molecules can bind in a shallow hydrophobic groove that runs alongside the protease cleavage site. Identification of these compounds lays the groundwork for pharmacological treatment for individuals harboring these hypersensitive DSP variants."

Journal • Cardiomyopathy • Cardiovascular • Immunology • Targeted Protein Degradation

High-throughput screening reveals GSK1838705A as a potent inhibitor of CAFs-promoted tumor progression in esophageal squamous cell carcinoma (ESMO 2023) - "Conclusions GSK1838705A is a potent inhibitor of CAFs which promote ESCC progression. The combination of GSK1838705A and chemoradiotherapy may be a promising strategy against ESCC."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CAFs

Inhibition of the epigenetically activated miR-483-5p/IGF-2 pathway results in rapid loss of meningioma tumor cell viability. (PubMed, J Neurooncol) - "Meningioma cell growth is critically dependent on autocrine miR-483/IGF-2 stimulation and the IGF-2 pathway provides a feasible meningioma treatment target."

Journal • Tumor cell • Brain Cancer • CNS Tumor • Meningioma • Oncology • Solid Tumor • IGF2 • MIR483

Novel Molecular Insight into the ESR1 Mutant/Adipocytes Crosstalk: a Pivotal Contribute of IGF1-R. (PubMed, FASEB J) - "Our data clearly demonstrated that adipocytes, the major compartment of tumor stroma, further sustain the aggressive malignant phenotype of mutant cells, mainly involving IGF-1R signaling pathway. Prospectively our findings address the use of an IGF-1R inhibitor to block the mutant/stroma cells interplay. In the era of precision medicine, the use of a specific IGF1R inhibitor may help to improve the outcome of BC patients expressing the ESR1 mutations, particularly in obese setting."

Journal • Breast Cancer • Genetic Disorders • Obesity • Oncology • Solid Tumor • ER • IGF1

Insulin-like signaling promotes limb regeneration in the Chinese mitten crab (Eriocheir sinensis). (PubMed, Fish Shellfish Immunol) - "Our experiment revealed that inhibition of ILS through injection of the InR inhibitor GSK1838705A at the blastema formation stage significantly reduced the limb regeneration rate compared to control group...These results suggest that ILS regulates limb regeneration in E. sinensis by promoting muscle growth and regeneration in response to autotomy stress. Thus, we identified a conserved insulin-like receptor in E. sinensis, and provide new evidence for the involvement of ILS in the regulation of limb autotomy and regeneration in crustaceans."

Journal • CDK1

IGF-1R inhibition induces MEK phosphorylation to promote survival in colon carcinomas. (PubMed, Signal Transduct Target Ther) - "Here, we discovered that prolonged treatment of colon cancer cells with IGF-1R inhibitors (BMS-754807 and GSK1838705A) stimulates p70 KDa ribosomal protein S6 kinase 1 (p70S6K1) activation, a well-known kinase signaling for cell survival. Furthermore, the combination of BMS-754807 and U0126 efficiently decreased the cell viability and increased cleaved caspase 3 and apoptosis in vitro and in vivo. Our data suggest that the treatment of colon tumor cells with IGF-1R inhibitors stimulates p70S6K1 activity via MEK1/2 to promote survival, providing a new strategy for colorectal cancer therapeutics."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • AKT1 • AKT2 • CASP3 • KRAS • MAP2K2 • PIK3CA • RPS6

Identification of SARS-CoV-2 Cell Entry Inhibitors by Drug Repurposing Using in silico Structure-Based Virtual Screening Approach. (PubMed, Front Immunol) - "Evidently, GR 127935 hydrochloride hydrate, GNF-5, RS504393, TNP, and eptifibatide acetate were found binding to virus binding motifs of ACE2 receptor. Additionally, KT203, BMS195614, KT185, RS504393, and GSK1838705A were identified to bind at the receptor binding site on the viral S-protein...Timely identification and determination of an effective drug to combat and tranquilize the COVID-19 global crisis is the utmost need of hour. Further, prompt in vivo testing to validate the anti-SARS-CoV-2 inhibition efficiency by these molecules could save lives is justified."

Journal • Immunology • Infectious Disease • Novel Coronavirus Disease • Pneumonia

GSK1838705a, an IGF-1R/ALK Inhibitor, Overcomes Resistance to Crizotinib in ALK-Positive ALCL (ASH 2019) - "Besides, we discovered that GSK1838705A inhibited the development of both crizotinib-sensitive and crizotinib-resistant ALCL tumors in the ALCL mouse model established by subcutaneous tumorigenesis. Based on the results of previous clinical trials, we put forward to use GSK1838705A as an alternative treatment strategy to overcome crizotinib-resistant ALCL."

ALK • IGF1R

Ramucirumab and GSK1838705A Enhance the Inhibitory Effects of Low Concentration Sorafenib and Regorafenib Combination on HCC Cell Growth and Motility. (PubMed, Cancers (Basel)) - "These combinations have the potential for decreased toxicity while simultaneously enhancing therapeutic effects. This potential decrease in toxicity is being explored in ongoing studies."

Biomarker • Journal

IGF-1R inhibition activates p70S6K1 to promote survival via MEK1/2 activation in colon cancer cells (AACR 2019) - "Prolonged treatment of IGF-1R resistant colon cancer cells with IGF-1R inhibitors (OSI-906, BMS-754807, and GSK1838705A) stimulates p70S6K1 activation, a well-known kinase signaling for cell survival. Furthermore, the combination of BMS754807 and U0126, a MEK1/2 inhibitor, effectively decreases the cell viability and increases apoptosis. Our data suggest that inhibition of MEK1/2 enhances the anti-proliferation effects of IGF-1R inhibitors, pointing out a new direction for overcoming the resistance of IGF-1R inhibition in colorectal cancer."