Developing a New Approach to Protein Degradation-Based Therapeutics
Our scientific team, which includes leading academic and drug discovery pioneers from the targeted protein degradation (TPD) field, has developed several completely novel mechanisms to remove disease-causing proteins from within cells to deliver potent efficacy in models of disease.
We have shown these novel mechanisms have potential to overcome many of the limitations seen with current TPD approaches, and to deliver transformational medicines to treat a wide range of disease.
The Power of Targeted Protein Degradation
The targeted protein degradation (TPD) approach offers a greatly improved way of modulating drug targets to treat disease using synthetic small molecule degraders which generate their effects through hijacking the cellular waste disposal process active within human cells, known as the ubiquitin-proteasome system (UPS).
TPD drugs effectively retrain and redirect this waste disposal process to actively seek out disease-causing proteins, leading to their rapid and sustained removal from the body leading to therapeutic benefits.
Members of the Amphista team were instrumental in laying foundations for the therapeutic applications of TPD approaches through landmark publications in 2015 and since then the field has moved rapidly with several agents now in clinical studies.
TPD-based therapeutic strategies can be applied to a wide range of highly validated drug targets and differ from most other drug modalities by not just inhibiting but also removing the pathogenic protein from the body often leading to more extensive, complete and sustained therapeutic benefits.
One powerful characteristic of protein degrading drugs is their ability to act as highly efficient catalysts meaning very low drug concentrations can deliver potent biological effects efficiently.
The Need for Next Generation Targeted Protein Degradation Therapies
The rapid development of TPD-based therapies has now allowed initiation of several clinical studies, offering the potential for transformational new therapies. During this time however, several potential limitations have begun to emerge which may slow the continued growth and success of TPD approaches.
There are 3 main areas where further advances would bring significant benefit to the field:
Existing TPD approaches do not work equally well for all drug targets and in all cells and tissues leading to limitations in scope.
Reduced Resistance Potential
Applying TPD approaches to anti-tumor therapies has highlighted significant potential risk of emerging resistance which may limit the durability of clinical response.
Improved Druglike Properties
The complex chemical structures of many current degrading therapeutics lead to limitations in their druglike propertiesincluding difficulty in routine compatibility with oral dosing regimens and an ability to enter the brain to treat diseases of the central nervous system.
Many of these limitations directly stem from the reliance of current TPD therapeutics on a small range of specific mechanisms including use of the ubiquitin E3 ligases VHL & cereblon. At Amphista we have discovered novel mechanisms which move beyond the current approaches used in the field which give us opportunity to also move beyond the current limitations.
The Amphista Strategy to Discovery Next Generation Targeted Protein Degradation Therapies
At Amphista, we recognise the need to identify new mechanisms to build on all of the powerful advantages of current TPD approaches while extending their reach and potential even further.
To do this, we use our in-depth knowledge of the UPS to identify suitable cellular proteins whose function can be redirected to deliver therapeutic degradation of specific disease-causing proteins. Then, using proprietary medicinal chemistry design we optimise ligands to these targets, and incorporate them into modular degrading molecules known as Amphistas able to deplete pathogenic proteins from cells in a highly efficient manner.
We have identified multiple new TPD mechanisms and degradation-inducing chemical strategies which can be used to remove a wide range of proteins from within cells. In all cases, the mechanisms and chemical warheads are proprietary to Amphista – our therapeutics do not use existing mechanisms which rely on the E3 ligases such as VHL or cereblon currently used by most in the TPD field.
The Benefits of Amphista Next Generation Targeted Protein Degradation Therapies
The mechanisms and Amphista degraders we use to induce degradation are carefully selected and designed to directly move beyond the limitations of current TPD approaches in areas such as scope, resistance potential and druglike properties.
Our mechanisms are selected to give the potential for robust efficacy across many cells and tissues. In head-to-head studies, we have shown Amphista degraders to give more robust cellular anti-tumor effects across broader ranges of tumor cells relative to current TPD strategies.
In addition, we have selected mechanisms which will be more challenging for tumor cells to develop resistance against, giving the potential for more durable clinical responses.
Finally, through our medicinal chemistry selection and optimisation of degrading molecules, we are able to introduce favourable druglike properties into Amphistas more readily than is possible with many existing TPD approaches. In particular, we have developed proprietary strategies and predictive processes to allow more routine introduction of attractive properties including good drug exposure after oral dosing and an ability to penetrate the brain to give potential to treat a wider range of diseases.
Amphista is advancing a portfolio of drug candidates, initially focused in oncology, to address a number of hard to treat tumor types.