CTSB-VEN-001
Cathepsin B-Activated Venetoclax Prodrug
Overview
Venetoclax-based regimens (azacitidine + venetoclax) deliver substantial responses in AML but are constrained by tumor lysis syndrome (TLS), an acute toxicity tied to rapid cytoreduction and high circulating drug exposure requiring dose ramp-up and intensive monitoring.
Unmet Medical Need
Efficacy is constrained by TLS risk and the need for slow oral ramp-up driven by high systemic Cmax. A therapy that decouples tumor kill from systemic Cmax would reduce TLS risk.
Therapeutic Hypothesis
IV, enzyme-activated small-molecule prodrug of venetoclax that is inert in circulation yet cleaved within lysosomes by Cathepsin B (CTSB)—enriched in AML blasts—releasing active venetoclax intracellularly. Uses cathepsin-cleavable dipeptide linkers (Val-Cit, Val-Ala) with PABC self-immolative spacer.
Computational Work Performed
- AlphaFold 3 for protein/ligand complex prediction (CTSB binding)
- DiffDock and AutoDock Vina 1.2 for dipeptide trigger docking
- GROMACS MD and MM/PBSA for stability/binding-energy analysis
- ADMET-AI for computational ADME/Tox screens
- DeepImmuno for peptide-level immunogenicity risk scanning
- Two lead constructs: PEG4-Val-Ala-PABC–VEN and PEG4-Val-Cit-PABC–VEN
Next Milestones (Success Criteria)
- 1pH-differential CTSB cleavage kinetics (pH 5.0 > pH 7.4)
- 2Human & mouse plasma stability (≥8h in human plasma)
- 3Selectivity: AML vs non-malignant cells (selectivity index ≥10×)
- 4IV PK showing low circulating free venetoclax Cmax
- 5Strong intratumoral activation with BCL-2 target engagement
Competitive Landscape
Oral BCL-2 inhibitors beyond venetoclax (lisaftoclax, sonrotoclax) claim ramp-up convenience but don't address enzyme-triggered intracellular release. ABBV-167 is an oral phosphate prodrug for solubility—distinct from CTSB-activated approach.
Key Differentiation
- Mechanism-differentiated: IV, lysosome-activated small molecule
- Solves TLS at the source by constraining systemic free venetoclax
- Concentrates activation in AML cells via CTSB-dependent release
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