salirasib (KD 032)

In summary, our investigation identifies a molecular vulnerability in c-Myc-driven TNBC, where Ras inhibition reinforces c-Myc-targeted therapy and potentiates immune checkpoint blockade, presenting a promising strategy to improve immunotherapy efficacy in TNBC.

To determine the sensitivity of KRAS or/and TP53-mutated cancer to KRAS, MEK1, or PLK1-targeted therapy, the inhibitors salirasib, trametinib, volasertib, and onvansertib were used in COAD cells with different KRAS and TP53 status. This treatment induced G1 and G2/M arrest, respectively, and showed the strongest synergistic effect in KRAS and TP53-mutated SW48 cells expressing mutant KRASG13D and transduced with TP53 shRNA, ultimately leading to apoptotic cell death. These effects are attributed to two-step inhibition mechanism that blocks the MAPK signaling pathway and disrupts mitosis in KRAS and TP53-mutated COAD cells.

Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity.

Moreover, treatment of tumor cells with Ras inhibitor salirasib prevented KLHL17-induced Ras/MAPK activity as well as tumor proliferation and migration...This study elucidates the role of KLHL17 in the development and progression of NSCLC using clinical samples and NSCLC cell lines. The results show that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating Ras/MAPK signaling pathway, and suggest that KLHL17 may be a novel therapeutic target for the treatment of NSCLC.

Therefore, we took a systematic approach to test how AQP1, AQP3 and AQP5, which are often over-/ectopically expressed in breast cancer, affect total viability of 3-dimensional (3D) breast cancer cell spheroids when treated with the conventional anticancer chemotherapies Cisplatin, 5-Fluorouracil (5-FU) and Doxorubicin, a Combination of the three drugs as well as the Combination plus the Ras inhibitor Salirasib. Thus, this study supports a significant role of AQPs in the response to conventional chemotherapies. Evaluating the role of individual proteins that contribute to resistance to chemotherapies is essential in advancing personalized medicine in breast carcinomas.

Moreover, treatment of tumor cells with Ras inhibitor salirasib prevented KLHL17-induced Ras/MAPK activity as well as tumor proliferation and migration. These results suggest that upregulated KLHL17 in NSCLC promotes the proliferation and migration of tumor by activating Ras/MAPK signaling pathway. Therefore, KLHL17 may be a novel therapeutic target for the treatment of NSCLC.

Computer-aided molecular modeling studies compared anticancer agents, salirasib and γ-tocotrienol, with the active site of galectin-3 and β-lactose (a known ligand)...In TS/A cells, 6-15 μM tocotrienol induced a dose-responsive increase in doxorubicin staining inside the nucleus...These findings also suggest that γ-tocotrienol may provide significant benefits in the prevention and/or treatment of metastatic breast cancer. This study was supported in part by funding from the Louisiana Cancer Foundation.

The ERK signaling cascade and downstream molecules are potential targets of action of AL in CCA.

In silico modeling revealed that Salirasib binds a putative allosteric site near the WPD loop of PRL-3, while Candesartan binds a potentially novel targetable site adjacent to the CXR motif. Inhibitor binding at either of these sites is predicted to trap PRL-3 in a closed conformation, preventing substrate binding and inhibiting function.

Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.

Computer-aided molecular modeling studies were carried out within the active site of galectin-3 based on the crystal structure (5EXO) obtained from the protein data bank with a known ligand, and anticancer agents (salirasib, γ-tocotrienol, and β-lactose) galectin-3 docking scores and amino acid interactions were determine...In summary, these results demonstrate for the first time that γ-tocotrienol treatment inhibits extracellular galectin-3 expression and disrupts galectin-3 carbohydrate binding and activation of +SA and TS/A mammary tumor cells. These findings also suggest that γ-tocotrienol may provide significant benefits in the prevention and/or treatment of metastatic breast cancer.

This combination strongly inhibited NF-κB activity and reduced pAkt and Bcl-2 levels in Panc-1 cells. SAL in combination with CEL may represent a new approach for effective inhibition of pancreatic cancer.