Synthetic HDAC Inhibitors
Logical Design
At Synthistat Ltd, we logically design our HDAC inhibitors based on structure based understanding of how specific components
(cap, linker and ZBG) in combination, yield the best pharmaceutical characteristics during in-silico testing.
Better Than The Best
Following the discovery that panobinostat outperforms sodium butyrate for lentiviral vector production, Synthistat decoded the specific structural features within panobinostat that yield this performance improvement and incorporate this understanding into our own proprietary HDACi designs.
We also identify and focus on developing candidates with better molecular docking scores than panobinostat.
The LVV Purpose
Our synthetic HDAC inhibitors are being developed for usage in lentiviral vector manufacturing and they are intended to super seed the usage of both sodium butyrate and panobinostat.
The Clinical Purpose
Our candidates also have classical drug like characteristics and better molecular docking scores than panobinostat. Therefore, they naturally have potential as pre-clinical candidates for the same medical indications that panobinostat and other HDACi are prescribed for, including oncological malignancies.
Multi-Targeting for Improved Efficacy
More advanced HDAC inhibitor designs also exhibit multi target activity and further inhibit D2R and/or BRD4. Enabling targeting of both epigenetic regulation, survival and transcriptional pathways in AML and solid cancers, for broader efficacy.
Ligand Pose Verification
Target activity of candidates is also supported by extensive ligand pose verification across independent docking campaigns, using multiple receptor structures and known inhibitor binding geometry rules. This enables us to identify and remove false positive hits from our candidate list.
Modified Producer Lines
Knock Out Cell Lines
There is the presence of specific endogenously expressed HIV-1 restriction factors, within HEK293 derived producer lines, that impede lentiviral vector biogenesis at various steps and can be supressed to support LVV production.
While a few have also been published upon by other groups, we have identified a list of 29 restriction factors, that have not been studied by other groups.
Scientifically Validated Approach
We have successfully validated our logical candidate selection approach by randomly selecting three KO targets and assessing the impact of their suppression during lentiviral vector production using a siRNA co-transfection protocol, where we transfect our packaging plasmids and siRNA together and then later assess the impact of target gene suppression upon LVV production.
Immediately Available Results
All three selection candidates were demonstrated to improve titres 2-3 fold versus control and the siRNA approach is also a viable approach which can be made GMP compliant and is readily available for research and commercial usage.
However, the knock out approach can be more economical and convenient.