GSK-2578215A / GSK - LARVOL DELTA

Inflammasome complex genes with clinical relevance suggest potential as therapeutic targets for anti-tumor drugs in clear cell renal cell carcinoma. (PubMed, Open Life Sci) - "Furthermore, our study revealed the potential of inflammasome complex genes as predictive markers for patient responses to various anti-tumor drugs, including Osimertinib, Ulixertinib, Telomerase Inhibitor IX, and GSK2578215A. These findings have significant clinical implications and offer opportunities for guiding treatment strategies and improving patient outcomes of ccRCC."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor

Microglial Sp1 induced LRRK2 upregulation in response to manganese exposure, and 17β-estradiol afforded protection against this manganese toxicity. (PubMed, Neurotoxicology) - "The results showed that Mn induced cytotoxicity, oxidative stress, and tumor necrosis factor-α production, which were attenuated by an LRRK2 inhibitor, GSK2578215A...Furthermore, E2 attenuated the Mn-induced Sp1 expression by decreasing the expression of Sp1 via the promotion of the ubiquitin-dependent degradation pathway, which was accompanied by increased protein levels of RING finger protein 4, the E3-ligase of Sp1, Sp1 ubiquitination, and SUMOylation. Taken together, our novel findings suggest that Sp1 serves as a critical TF in Mn-induced LRRK2 expression as well as in the protection afforded by E2 against Mn toxicity through reduction of LRRK2 expression in microglia."

Journal • CNS Disorders • Inflammation • Movement Disorders • Oncology • Parkinson's Disease • Targeted Protein Degradation • LRRK2 • SP1 • TNFA

LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells. (PubMed, Oxid Med Cell Longev) - "Human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) were treated with rotenone in the presence or absence of the LRRK2 kinase inhibitor GSK2578215A (GSK-KI) for 48 h...Mice were intraperitoneally injected with rotenone and MLi-2 (LRRK2 kinase inhibitor) once every two days for two weeks...Rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, which enhanced α-syn accumulation. However, the administration of an LRRK2 kinase inhibitor rejuvenated rotenone-induced cellular senescence."

Journal • CNS Disorders • Metabolic Disorders • Movement Disorders • Parkinson's Disease • CDKN1A

LRRK2 inhibition potentiates PARP inhibitor cytotoxicity through inhibiting homologous recombination-mediated DNA double strand break repair. (PubMed, Clin Transl Med) - "Here, we found that GSK2578215A, a high-selective and effective leucine-rich repeat kinase 2 (LRRK2) inhibitor, or LRRK2 depletion suppresses HR preventing the recruitment of RAD51 to DNA damage sites through disruption of the interaction of RAD51 and BRCA2. Moreover, LRRK2 inhibition or depletion increases the susceptibility of ovarian cancer cells to Olaparib in vitro and in vivo...All these findings indicate ovarian cancers expressing high levels of LRRK2 are more resistant to treatment potentially through promoting HR. Furthermore, combination treatment with an LRRK2 and PARP inhibitor may be a novel strategy to improve the effectiveness of LRRK2 expression ovarian cancers."

Journal • Oncology • Ovarian Cancer • Solid Tumor • BRCA2 • RAD51

Crohn's and Parkinson's Disease-Associated LRRK2 Mutations Alter Type II Interferon Responses in Human CD14 Blood Monocytes Ex Vivo. (PubMed, J Neuroimmune Pharmacol) - "IFN-γ potently enhanced TNFA, IL12, HLADRA1 and LRRK2 expression, which was suppressed by FK506, a calcineurin-specific inhibitor, but further enhanced by LRRK2-specific kinase inhibitor (GSK2578215A)...These data demonstrate that CD-associated LRRK2 mutations are significant modifiers of innate immune response in CD14 monocytes, and PD-associated LRRK2 mutation may contribute to reduced antigen presentation response. Graphical Abstract."

Journal • CD14 • IL12A