Science

DUB Platform

Overcoming challenges in developing DUB inhibitors

Mission Therapeutics has built a world-leading proprietary DUB platform for the discovery and development of first-in-class drugs that selectively target specific disease-associated DUBs.

Overcoming challenges in developing DUB inhibitors

DUBs are a large family of proteins expressed in many different human cells, which are implicated in numerous diseases. Consequently, they have attracted much interest as drug targets. However, the advancement of potent DUB inhibitors suitable for clinical development initially proved challenging. One difficulty has been identifying small molecule drugs which inhibit DUBs in a highly-targeted fashion, i.e. with high specificity and selectivity.

Ever since Mission was founded in 2011, our scientists have been focused solely on the biology of DUBs and the development of specific and highly potent small molecule drugs that inhibit the activity of specific DUB targets. We believe that our singular focus has enabled us to solve many issues that have previously made the development of DUB drugs challenging.

Mission’s proprietary DUB platform:

  • Gives deep insights into DUB target validation
  • Offers DUB-specific screening cascades
  • Is based on novel, unique chemistry
  • Has created a growing library of small-molecule DUB inhibitors

Two of these inhibitors, MTX652 and MTX325. which both inhibit the DUB USP30, have been cleared for clinical trials – with MTX652 already in the clinic. Others are in pre-clinical development.

Mission Therapeutics

DUB Platform

Expert insights into DUB target validation

Mission has designed and developed rigorous target identification screening and validation cascades to ensure our efforts are focused on selectively and specifically inhibiting the right DUBs.

We are systematically screening against individual DUBs in areas of unprecedented, novel biology and pathology with significant commercial potential. We use patient selection strategies to enable early proof-of-concept in indications with high unmet medical need.

DUB-specific

Screening cascade

Mission has developed a robust screening cascade, designed to eliminate false positives as early as possible and focus on genuine drug candidates from the outset. We develop and use bespoke biochemical and cellular assays that are as closely related as possible to physiological conditions. This involves purifying full-length DUBs from mammalian cells to ensure proper folding, post-translational modifications and co-factors, as well as using substrates closely related to the natural DUB substrates, e.g. incorporating an isopeptide linkage between ubiquitin and, ideally, a peptide derived from the DUB’s cellular target.

A number of orthogonal, confirmatory assays are also used to eliminate false positives at an early stage and our proprietary, cellular target engagement assays are performed as early as possible to confirm specific inhibition of DUBs in cells. The drug discovery cascade is accelerated by iterative design-make-test cycles, driven by our in-house medicinal chemistry team, and guided by molecular modelling and structural biology.

Designed to overcome specificity challenges – proprietary small-molecule DUB inhibitor library

Using a novel approach, our in-house medicinal chemistry team developed a DUB-specific compound library consisting of more than 17,000 molecules with exclusive and proprietary chemotypes. This has provided an outstanding starting point for the development of drug-like lead compounds that do not contain toxicophores and fully comply with the ‘rule of 5’ criteria. This proprietary library asset has seeded many of our DUB therapeutic projects. The library has generated a high number of hits for particular DUB targets, enabling rapid progress in the identification of optimised leads with candidate drug levels of potency, selectivity, pharmacokinetics and in vivo efficacy.

Proprietary chemistry platform;

generates innovative, first-in-class DUB inhibitors

Mission’s chemistry platform has been optimised for therapeutically important members of the DUB enzyme family by designing molecules containing low-reactivity covalent functional groups. These proprietary chemotypes are tractable, drug-like and ligand efficient. By making changes to the architecture of these compounds, Mission’s chemists have been able to specifically inhibit many different DUBs from across the DUB phylogenetic tree.

  • Targeted covalent inhibitors containing reversible, low-reactivity bond-forming functional groups
  • >100-fold selectivity achieved against a large panel of DUBs and related enzymes
  • >30 chemistry patent applications filed to date

Clinical development and patient selection strategy

Clinical development and patient selection strategies are central to all of Mission’s programs. These are overseen by our CMO, Suhail Nurbhai, who is supported and guided by experienced, international clinical advisors.

For our programs, a patient selection and/or biomarker strategy will be incorporated as early as possible to increase the chances of obtaining early proof of clinical signs of activity.

We also collaborate with clinical consulting companies at various stages of the discovery and development process to ensure our programs are aimed at viable markets in areas of unmet clinical need.

IP

Mission is protecting its platform and pipeline with many patent filings covering target validation, proprietary assay development, composition-of-matter and patient selection/biomarker strategies.

References

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