SB-590885

Type I inhibitor SB590885 is roughly equipotent across RAF isoforms and, as expected, type I.5 inhibitors are typically most potent against BRAFV600E. Crystal structures of CRAF in complex with type I.5 inhibitor PLX4720 reveal an asymmetric CRAF dimer with one CRAF subunit bound in the inactive state and the second bound in an αC-helix-in, active conformation with an altered inhibitor pose. Our findings have important implications for understanding the pharmacology of current RAF inhibitors and will inform development of new agents with distinct isoform selectivity.

The expression of USP2 was positively correlated with sensitivity to small-molecule drugs, including entinostat, SB590885, and PF-562,271. USP2 acts as a negative regulator of gastric cancer progression. Consequently, USP2 has the potential to be utilized as a therapeutic target to improve the clinical prognosis and survival rates of patients.

Type I inhibitor SB590885 is roughly equipotent across RAF isoforms and, as expected, type I.5 inhibitors are typically most potent against BRAFV600E. Crystal structures of CRAF in complex with type I.5 inhibitor PLX4720 reveal an asymmetric CRAF dimer with one CRAF subunit bound in the inactive state and the second bound in an aC-helix-in, active conformation with an altered inhibitor pose. Our findings have important implications for understanding the pharmacology of current RAF inhibitors and will inform development of new agents with distinct isoform selectivity.

Lifirafenib (Type II) + encorafenib (Type I½) was highly synergistic against both NRAS - and KRAS -mutant lines, while synergy of lifirafenib + SB590885 (Type I) was specific to NRAS -mutants. Assessment of leukemia burden in bone marrow and spleen during treatment further showed site-specific efficacy against circulating and spleen-resident blasts for both combinations. In summary, we report that our structure based-modelling approach can effectively identify novel, non-obvious, and well-tolerated RAFi combinations that are highly effective against in vitro and in vivo models, thereby suggesting alternative potential therapeutic strategies for high-risk RAS -mutant AML.

Exploring essential prognostic-risk genes and their association with the prognosis, diagnostic efficacy, and risk-group prediction may provide substantial clues for targeting the breast cancer stromal key-risk genes.

We also used Gene Set Cancer Analysis (GSCA) to predict a serious of small molecule CEP55 targeted drugs, such as AZ628, SB52334, SB590885, A-770,041, AZD7762, Elesclomol, panobinostat, BRD-A94377914, and LRRK2-IN-1. Our study indicated that CEP55 overexpression in most caner types was associated with poor prognosis. Notably, CEP55 was closely relevant to immune cell infiltration and impacted the response to immunotherapy and small molecule drugs against cancers.

Additionally, a high level of CTHRC1 was correlated with decreased sensitivity to antitumor drugs (vemurafenib, PLX-4720, dabrafenib, and SB-590885) targeting the BRAF(V600E) mutation. This study provides evidence of a significant correlation between CTHRC1 and the BRAF(V600E) mutation, suggesting its potential utility as a diagnostic and prognostic biomarker in human colon cancer, thyroid cancer, and melanoma.

Our study elucidated the possible role of TRP family genes in cancer progression and provided insights for further studies on TRP family genes as potential pan-cancer targets to develop diagnostic and therapeutic strategies.

Finally, we proposed 16 candidate repurposing drugs YM201636, masitinib, SB590885, GSK1070916, GSK2126458, ZSTK474, dasatinib, fedratinib, dabrafenib, methotrexate, trametinib, tubastatin A, BIX02189, CP466722, afatinib, and belinostat for BC through molecular docking analysis. Using BC cell lines, we validated that masitinib inhibits the mTOR signaling pathway and induces apoptotic cell death. Therefore, the proposed results might play an effective role in the treatment of BC patients.

The BRAF signature may better help guide targeted therapy for melanoma, and such a framework can be applied to other cancers and mutations to provide more information than mutation status alone.