VivaMed Biopharma
Back to Asset Listing
VM-BRAF-038Computational Validation Complete

Next-Gen BRAF V600E Inhibitors

Metabolic Soft-Spot Swap for QD Dosing

BRAF V600E/K-mutant Tumors (Melanoma, NSCLC)Small Molecule
QD dosing with lower pyrexia

Overview

BRAF V600E-mutant malignancies are treated with BRAF+MEK combinations (dabrafenib+trametinib) with proven benefit but BID dabrafenib dosing (t½ ≈ 8h) and high pyrexia burden (≈52-71%) leading to dose interruptions and reductions.

Unmet Medical Need

A QD, better-tolerated BRAF inhibitor would meaningfully improve adherence and quality of life. Current standard requires BID dosing with significant pyrexia management burden.

Therapeutic Hypothesis

Replace the para-tert-butyl 'metabolic soft spot' in dabrafenib with shape-matched, rigid sp³ bioisosteres (oxanorbornyl, oxabicyclohexyl) to: (i) block the dominant metabolic route, (ii) lower lipophilicity/improve solubility, (iii) maintain binding to BRAF V600E.

Computational Work Performed

  • AlphaFold3-class structure prediction for BRAF V600E
  • 800 DiffDock poses generated across 8 analogs (100 per candidate)
  • ADMET-AI 99-feature property predictions per compound
  • eTOXlab multi-endpoint toxicity predictions
  • 3 synthesis-ready leads identified: DBF-OXA-NB, DBF-CF2, DBF-OBH

Next Milestones (Success Criteria)

  • 1
    BRAF V600E enzyme IC₅₀ and A375 viability EC₅₀ within 3× dabrafenib
  • 2
    Selectivity vs ARAF/CRAF (>30× vs MEK1)
  • 3
    HLM/mHep stability ≥2× t½ vs dabrafenib
  • 4
    hERG/CiPA early panel with clean cardiac safety margins
  • 5
    Ex-vivo cytokine assay (IL-1β/IL-6): <50% of dabrafenib+trametinib signal

Competitive Landscape

Paradox breakers (PLX8394), Type-II/pan-RAF inhibitors (tovorafenib, naporafenib, belvarafenib). Current SOC combos: dabrafenib+trametinib (pyrexia-prone), vemurafenib+cobimetinib, encorafenib+binimetinib (lower pyrexia ~18%).

Key Differentiation

  • V600-focused inhibitor with QD PK and attenuated pyrexia biology
  • Proprietary heterobicyclic sp³ replacements at the para-t-Bu site
  • Practical differentiation within the approved combination paradigm

Interested in This Asset?

Contact our licensing team to discuss partnership opportunities, access detailed data packages, and explore collaboration terms.

Contact Licensing TeamView All Assets