RAF265 / Novartis - LARVOL DELTA

Antitumor effects of CEP32496 on urothelial carcinoma with BRAF mutation (V595E) in dogs. (PubMed, Can J Vet Res) - "For reference, 7 BRAF inhibitors, including GDC0879, PLX4720, encorafenib, vemurafenib, dabrafenib, AZ628, and RAF265, were also evaluated. In the xenograft model, 10 mg/kg body weight of CEP32496 resulted in a significant decrease (P < 0.05) in tumor growth in mice, with severe and extensive necrosis on histopathological examination. These results suggested that CEP32496 exerts antitumor effects on both cell proliferation and tumor growth in UC with V595E."

Journal • Oncology • Solid Tumor • Urothelial Cancer • BRAF

Identification of RNA binding proteins targeting TP53, RB1 and PTEN in colorectal cancer as potential biomarkers for diagnosis, drug resistance, sensitivity and prognosis. (PubMed, Discov Oncol) - "Drug sensitivity analyses using GDSC and CCLE datasets revealed exploratory and unadjusted associations between elevated NOP56, FBL, and FUS expression and increased sensitivity to Irinotecan, Nilotinib, and Raf265. Importantly, these CLIP-seq interactions reflect physical binding potential rather than direct functional regulation of target gene expression. Overall, 22 RBPs were identified as candidate binding-associated regulators of key tumor suppressors, and seven RBPs involved in prominent pathways were identified as candidate prognostic biomarkers requiring further validation in independent cohorts before any clinical application can be considered in CRC, although these findings remain exploratory and require further functional validation."

Biomarker • Journal • Colorectal Cancer • Inflammatory Arthritis • Oncology • Solid Tumor • EIF4A3 • FUS • IGF2BP1 • NOP56 • PTEN • RB1 • TP53

Targeting USP10/SCD1 axis by RAF265 suppresses lipogenesis and induced ferroptosis in head and neck squamous cell carcinoma. (PubMed, Cell Death Discov) - "Notably, we discover that RAF265, a compound already approved by the FDA, effectively inhibits USP10 activity, leading to decreased SCD1 expression and lipogenesis, which then suppresses tumor growth and enhances ferroptosis in both in vitro and in vivo models of HNSCC. Collectively, these results underscore the critical role of the E2F4/USP10/SCD1 pathway in modulating ferroptosis and driving HNSCC progression, suggesting that targeting this axis with RAF265 may offer a promising strategy for therapeutic intervention in this malignancy."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Targeted Protein Degradation • SCD • USP1

Retraction Note: Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26+ cancer stem cells in colorectal carcinoma. (PubMed, Mol Cancer) - No abstract available

Journal • Preclinical • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • DPP4

Identification of molecular targets from the interactome of primary sclerosing cholangitis and their therapeutic modulation (FFS-AIH 2025) - "In silico screening identified their ligands BGB-283 and RAF-265, which downregulated NF-kB signature expression in PSC organoids. GW-493838 combined with BMS270394 notably downregulated both TGF-beta and Notch signatures. We discovered perspective molecular targets in PSC and showed the impact of their predicted small molecule ligands on transcriptomes of primary PSC cholangiocyte organoids. OP and CF share first authorship MT and TR share senior authorship"

Cholestasis • Fibrosis • Gastroenterology • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Primary Biliary Cholangitis • ABCB4 • CD1C • CD36 • ITGAX • KRT19 • NFKB1 • NRP1 • SCARB1 • SLIT2 • TGFB1 • VEGFA

A Drug Repositioning Approach Reveals Ergotamine May Be a Potential Drug for the Treatment of Alzheimer's Disease. (PubMed, J Alzheimers Dis) - "In further analysis by molecular dynamics simulations, both drugs exhibited reasonable stability. Our work indicated that ergotamine and RAF-265 may be potential candidates for treating AD."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Identification of Collagen-Suppressive Agents in Keloidal Fibroblasts Using a High-Content, Phenotype-Based Drug Screen. (PubMed, JID Innov) - "The most collagen suppressive agents were CGP60474 ( = 0.36), KIN001-244 ( = 0.55), and RAF265 ( = 0.58). The top candidate, CGP60474, consistently abolished collagens I and VII production, exhibited minimal global toxicity, and induced a fivefold increase in phosphorylated extracellular signal-regulated kinase. This proof-of-concept high-content screen can identify drugs that appear to target critical keloidal pathophysiology-collagen secretion."

Journal • Fibrosis

MAPK pathway alterations as a targetable vulnerability in bladder cancer. (ASCO-GU 2024) - "Currently, cisplatin-based chemotherapy and anti-PD1/PD-L1 agents are the backbone of systemic therapy in BC, yet only a subset of patients respond... The activity of the activity of RAF inhibitors (including RAF265 and the novel RAF dimerization inhibitor LXH254) was tested in BC cell lines with diverse MAPK pathway alterations including RAF1 amplification and NRAS mutations...There was a significant reduction in tumor volumes of UMUC9-engrafted mice treated with RAF265 (n=10) or RAF265 plus trametinib (n=8) compared to vehicle controls (n=14)... We sought to explore the vulnerabilities incurred by MAPK pathway alterations in BC. We tested the activity of a RAF inhibitors in BC cell lines with RAF1 amplifications and NRAS mutations and found that MAPK pathway-altered models displayed increased sensitivity to RAF inhibition compared to MAPK-unaltered models. We further showed this sensitivity in vivo with RAF1-amplified mouse xenografts and elucidated the synergistic..."

IO biomarker • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • NRAS

An open source plant kinase chemogenomics set. (PubMed, Plant Direct) - "Compound RAF265 (CHIR-265), previously shown to bind the human kinase BRAF (B-Raf proto-oncogene, serine/threonine kinase), also binds to nine highly conserved rice kinases tested. The binding of human and rice kinases to the same compound suggests that human kinase inhibitor sets will be useful for dissecting the function of plant kinases."

Journal • Oncology • BRAF

Small-Molecule RAF265 as an Antiviral Therapy Acts against PEDV Infection. (PubMed, Viruses) - "RAF265 also presented potent inhibitory activity against viral infection by SARS-CoV-2-pp and SARS-CoV-pp. The present work may provide a starting point for further progress toward the development of antiviral strategies effective against coronavirus PEDV."

Journal • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Small Molecule RAF265 as an Antiviral Therapy Acts Against HSV-1 by Regulating Cytoskeleton Rearrangement and Cellular Translation Machinery. (PubMed, J Med Virol) - "RAF265 mediated cytoskeleton rearrangement and targeted the host cell's translation machinery, which suggests that the antiviral activity of RAF265 may be attributed to a dual inhibition strategy. This work offers a starting point for further advances toward clinical development of antivirals against HSV-1."

Journal • Herpes Simplex • Infectious Disease • Oncology • BRAF

B-Raf inhibitor vemurafenib counteracts sulfur mustard-induced epidermal impairment through MAPK/ERK signaling. (PubMed, Drug Chem Toxicol) - "Other tested B-Raf inhibitors, both type-I (dabrafenib and encorafenib) and type-II (RAF265 and AZ628), also exhibited potent therapeutic effects on SM-exposed HaCaT cells. Furthermore, vemurafenib partially improved cutaneous damage in a mouse ear vesicant model. Collectively, our results provide evidence that the B-Raf inhibitor vemurafenib is a potential therapeutic agent against SM injury, and oncogenic B-Raf might be an exciting new therapeutic target following exposure to mustard vesicating agents."

Journal • Immunology • Inflammation • Oncology • BRAF

CHIR-265-MEL01: A Study to Evaluate RAF265, an Oral Drug Administered to Subjects With Locally Advanced or Metastatic Melanoma (clinicaltrials.gov) - P1/2; N=104; Completed; Sponsor: Novartis Pharmaceuticals; Phase classification: P2 ➔ P1/2

Clinical • Phase classification • Melanoma • Oncology • Solid Tumor • BRAF

Therapeutic potential of combined BRAF/MEK blockade in BRAF-wild type preclinical tumor models. (PubMed, J Exp Clin Cancer Res) - "Overall, our data indicate that RAF inhibition-induced paradoxical MAPK activation could be exploited for therapeutic purposes by simultaneously targeting both RAF and MEK (and potentially EGFR family members) in appropriate molecular contexts. KRAS mutation per se does not effectively predict therapeutic synergism and other biomarkers need to be developed to identify patients potentially deriving benefit from combined BRAF/MEK targeting."

Biomarker • Journal • Preclinical • Biosimilar • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

RAF265 inhibits the growth of advanced human melanoma tumors (Clin Cancer Res) - P=NA, N=34; Nine of the 17 tumors that successfully implanted were mutant BRAF (BRAFV600E/K), while 8 of 17 were BRAF wild-type (BRAFWT); Tumor implants from seven pts responded to RAF265 treatment with >50% reduction in tumor growth; While response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki67, cyclin D1 & PLK1, & induction of the apoptosis mediator BIM

Preclinical-animal • Melanoma • Oncology

The combination of RAF265, SB590885, ZSTK474 on thyroid cancer cell lines deeply impact on proliferation and MAPK and PI3K/Akt signaling pathways (Invest New Drugs) - "...combination index revealed an interesting synergistic effect of combination regimen (RAF265 + ZSTK474 and SB590885 + ZSTK474) in almost all cell lines. Moreover this synergistic effect was particularly evident by Western blot, whereas dual MAPK and PI3K/Akt inhibition was detected."

Preclinical • Oncology

MEK162 and RAF265 in Adult Patients With Advanced Solid Tumors Harboring RAS or BRAFV600E Mutations (clinicaltrials.gov) - P1; N=69; Completed; Sponsor: Novartis Pharmaceuticals; Active, not recruiting ➔ Completed

Clinical • Trial completion