ly3009120 and Neoplasms

Oncogenic BRAF kinase deregulates the ERK signaling pathway in a large number of human tumors. FDA-approved BRAF inhibitors for BRAFV600E/K tumors have provided impressive clinical responses extending survival of melanoma patients. However, these drugs display paradoxical activation in normal tissue with BRAFWT due to RAF transactivation and priming, acquired drug resistance, and limited clinical effectiveness in non-V600 BRAF-dependent tumors, underscoring the urgent need to develop improved BRAF inhibitors. This review provides an overview of recent structural and biochemical insights into the mechanisms of BRAF regulation by BRAF inhibitors that are linked to their clinical activity, clinical liabilities, and medicinal chemistry properties. The effectiveness and challenges of structurally diverse next generation RAF inhibitors currently in preclinical and clinical development are discussed, along with mechanistic insights for developing more effective RAF inhibitors targeting different oncogenic BRAF conformations.

Topics: Animals; Drug Discovery; Humans; Mutation; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf

Frequent oncogenic mutations have been identified in MAPK (mitogen-activated protein kinase) signaling pathway components. As a result, MAPK pathway is associated with human cancer initiation, in particular RAF (rapidly accelerated fibrosarcoma) component. The mutation in RAF component leads to auto-activation of MAPK signaling pathway, stimulating the uncontrolled cell growth and proliferation. In last few years, diverse chemical scaffolds have been identified as RAF inhibitors. Most of these scaffolds show potent anti-cancer activity. The present review highlights the recent investigations of RAF inhibitors during the last five years.

Topics: Animals; Antineoplastic Agents; Drug Discovery; Humans; MAP Kinase Signaling System; Models, Molecular; Neoplasms; Protein Kinase Inhibitors; raf Kinases

Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (

Topics: Animals; Azetidines; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dogs; Drug Combinations; Drug Synergism; Female; Humans; Madin Darby Canine Kidney Cells; Mice, Nude; Molecular Structure; Mutation; Neoplasms; Phenylurea Compounds; Piperidines; Protein Binding; Protein Kinase Inhibitors; Quinazolinones; raf Kinases; Structure-Activity Relationship; Xenograft Model Antitumor Assays

LY3009120 is a pan-RAF and RAF dimer inhibitor that inhibits all RAF isoforms and occupies both protomers in RAF dimers. Biochemical and cellular analyses revealed that LY3009120 inhibits ARAF, BRAF, and CRAF isoforms with similar affinity, while vemurafenib or dabrafenib have little or modest CRAF activity compared to their BRAF activities. LY3009120 induces BRAF-CRAF dimerization but inhibits the phosphorylation of downstream MEK and ERK, suggesting that it effectively inhibits the kinase activity of BRAF-CRAF heterodimers. Further analyses demonstrated that LY3009120 also inhibits various forms of RAF dimers including BRAF or CRAF homodimers. Due to these unique properties, LY3009120 demonstrates minimal paradoxical activation, inhibits MEK1/2 phosphorylation, and exhibits anti-tumor activities across multiple models carrying KRAS, NRAS, or BRAF mutation.

Topics: Antineoplastic Agents; Cell Line, Tumor; Dimerization; Humans; MAP Kinase Signaling System; Mitogen-Activated Protein Kinases; Mutation; Neoplasms; Phenylurea Compounds; Phosphorylation; Protein Isoforms; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-raf; Pyrimidines; ras Proteins; Signal Transduction