Givinostat's Potency on HDAC 2 and 4
Givinostat is a potent pan-HDAC inhibitor that has strong activity against both HDAC2 and HDAC4, though specific IC50 values for these individual isoforms are not directly provided in the available evidence.
Mechanism of Action and HDAC Inhibition Profile
Givinostat (ITF2357) is an orally available histone deacetylase inhibitor that targets multiple HDAC isoforms across both class I (which includes HDAC2) and class II (which includes HDAC4) 1. As a pan-HDAC inhibitor, it has a broad spectrum of activity against multiple HDAC enzymes.
The evidence indicates that:
- Givinostat functions as a potent inhibitor of both class I and class II HDACs 1
- It demonstrates activity similar to other pan-HDAC inhibitors like vorinostat, which is known to target HDAC1, 2,3, and 6 1
- Its mechanism involves post-translational modification of both histone and non-histone proteins 1
Clinical Applications Demonstrating HDAC Inhibition
Givinostat's potent HDAC inhibitory activity is evidenced by its clinical applications:
- Recently approved by the FDA (March 2024) for Duchenne muscular dystrophy in patients 6 years and older 2
- Shows significant activity in polycythemia vera patients, particularly those unresponsive to hydroxycarbamide 3, 4
- Demonstrates anti-neoplastic effects in glioblastoma models through HDAC inhibition 5
Comparative Potency
While specific IC50 values for HDAC2 and HDAC4 are not directly provided, we can make some inferences:
- Givinostat shows similar clinical activity to vorinostat, which is used as a reference HDAC inhibitor with known activity against HDAC1, 2,3, and 6 1
- In pharmacodynamic studies, givinostat demonstrates potent biological effects at relatively low concentrations (50-100 mg/day dosing in clinical studies) 4
- In glioblastoma models, low doses (≤1 μM) were sufficient to induce autophagy-mediated cell death and differentiation 5
Pharmacokinetic Considerations
The pharmacokinetic profile of givinostat provides additional insights into its potency:
- Givinostat follows a two-compartment model with first-order elimination 6
- It efficiently crosses the blood-brain barrier, indicating good tissue penetration 5
- Weight-based dosing produces systemic exposure of 554-641 ng·h/mL 6
Clinical Implications
The potent HDAC inhibitory activity of givinostat translates to several clinical benefits:
- In polycythemia vera, complete or partial response was observed in 50-55% of patients resistant to hydroxycarbamide 4
- Control of pruritus was achieved in 64-67% of polycythemia vera patients 4
- In glioblastoma models, it inhibited neurosphere formation from patient-derived stem cells 5
Safety Profile
Givinostat's safety profile is relevant when considering its potency:
- The combination of givinostat and hydroxycarbamide was well tolerated with grade 3 adverse events in only 4.5% of patients 4
- Platelet count monitoring is recommended due to an average decrease of 45% from baseline 6
- After 6 months of treatment, approximately 14-15% of patients had platelet counts <75 × 10^9/L 6
While the evidence doesn't provide specific IC50 values for HDAC2 and HDAC4, givinostat's clinical efficacy and classification as a potent pan-HDAC inhibitor suggest significant activity against both these isoforms.