SB-590885 / GSK, Zunyi Medical University - LARVOL DELTA

Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia (ASH 2024) - "Mice were then treated with vehicle, lifirafenib (LIF; 10 mg/kg, p.o.), encorafenib (ENCO; 20 mg/kg, p.o.), SB590885 (SB; 25 mg/kg, IP), or either drug combination (LIF + ENCO or LIF + SB). Conclusions We used a structural biology and in silico computational modelling approach to identify novel, non-obvious kinase inhibitor combinations. Computational approaches were notably validated by the high efficacy of well-tolerated treatments in a pre-clinical mouse model, suggesting potential translatability for treating RAS-mutant AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • AFDN • KMT2A • KRAS • NRAS • PTPRC • RAS

Selectively Inhibition of MAPK pathway showed positive effects on Porcine embryo-derived stem cells pluripotency. (PubMed, Sci Rep) - "Screening key molecular target inhibitors in three branches identified the B-RAF inhibitor SB590885 (SB59) as enhancing porcine embryonic stem cell pluripotency and facilitating lineage differentiation. Further analysis revealed a significant correlation between the expression level of phosphorylated ERK (p-ERK) and the developmental potential of porcine embryo-derived stem cells. These findings contribute valuable insights into the understanding of regulatory mechanism of porcine pluripotency."

Journal • Preclinical • BRAF

Characterization and inhibitor sensitivity of ARAF, BRAF, and CRAF kinases. (PubMed, J Biol Chem) - "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."

Journal • Melanoma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • ARAF • BRAF

The downregulation of ubiquitin-specific peptidase 2 indicates a poor prognosis and promotes the progression of gastric cancer through focal adhesion and ECM pathway signaling. (PubMed, Sci Rep) - "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."

Journal • Gastric Cancer • Microsatellite Instability • Oncology • Solid Tumor • Targeted Protein Degradation • MSI

Characterization and inhibitor sensitivity of ARAF, BRAF, and CRAF complexes. (PubMed, bioRxiv) - "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."

Journal • Melanoma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • ARAF • BRAF

A structure-based modelling approach identifies effective drug combinations for RAS-mutant acute myeloid leukemia. (PubMed, bioRxiv) - "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."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • KRAS • NRAS • RAS

Exploration of crucial stromal risk genes associated with prognostic significance and chemotherapeutic opportunities in invasive ductal breast carcinoma. (PubMed, J Genet Eng Biotechnol) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • ADAM8 • CD86 • IGFBP6 • MMP11

Prognosis prediction and drug guidance of ovarian serous cystadenocarcinoma through mitochondria gene-based model. (PubMed, Cancer Genet) - "To summarize, we established a novel 7 MRGs - based risk score model that could be utilized for prognosis prediction and chemosensitivity assessment in OSC patients."

Journal • Metabolic Disorders • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • ACOT13

Pan-cancer analysis of oncogenic role of CEP55 and experiment validation in clear cell renal cell carcinoma. (PubMed, Sci Rep) - "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."

IO biomarker • Journal • Pan tumor • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CCNA2 • CD4 • CDK1 • CEP55 • KIF11 • LRRK2 • PCNA

CTHRC1 is associated with BRAF(V600E) mutation and correlates with prognosis, immune cell infiltration, and drug resistance in colon cancer, thyroid cancer, and melanoma. (PubMed, Biomol Biomed) - "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."

Immune cell • IO biomarker • Journal • Colon Cancer • Colorectal Cancer • Endocrine Cancer • Gastrointestinal Cancer • Melanoma • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF

Using structure-based modelling to identify effective drug combinations in high-risk acute leukaemia (EACR-AACR 2024) - "Combined lifirafenib (Type 2) and encorafenib (Type 1.5) was highly synergistic against both NRAS- and KRAS-mutant lines (Loewe additivity scores = 7.9-31.1), while synergy observed for combined lifirafenib and SB-590885 (Type 1) was specific to NRAS-mutant lines (Loewe additivity scores = 21.4-27.9). Conclusion We have utilized a systems biology approach to identify novel, non-obvious kinase inhibitor combinations, providing a promising therapeutic avenue for treating RAS-mutant AML. Efficacy of these combinations in vivo will provide rationale for promoting these combinations into clinical use."

Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • KRAS • NRAS • PTPRC

Pan-Cancer Analysis of the TRP Family, Especially TRPV4 and TRPC4, and Its Expression Correlated with Prognosis, Tumor Microenvironment, and Treatment Sensitivity. (PubMed, Biomolecules) - "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."

Biomarker • IO biomarker • Journal • Pan tumor • Tumor microenvironment • Bladder Cancer • Oncology • TRPC4

Bioinformatics and network-based screening and discovery of potential molecular targets and small molecular drugs for breast cancer. (PubMed, Front Pharmacol) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • AURKA • BIRC5 • CDK1 • EGFR • KDM5B • MIR16 • MIR23b • MIR34A • SOX2 • TOP2A • TP63

Cardiomyocyte BRAF and type 1 RAF inhibitors promote cardiomyocyte and cardiac hypertrophy in mice in vivo. (PubMed, Biochem J) - "We assessed the effects of activated BRAF in the heart using mice with tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene...The experimental Type 1 RAF inhibitor, SB590885, and/or encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted hypertrophy, consistent with a 'RAF paradox' effect...In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce hypertrophy, and Type 1 RAF inhibitors promote hypertrophy via the 'RAF paradox'. Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology • Oncology • BRAF

A B-Raf V600E gene signature for melanoma predicts prognosis and reveals sensitivity to targeted therapies. (PubMed, Cancer Med) - "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."

Journal • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF • EGFR