Discovery Programmes

TNF-α Converting Enzyme Inhibitors
Malaria
Nuclear Hormone Receptors

TNF-α Converting Enzyme Inhibitors

Background

The action of Tumor Necrosis Factor alpha (TNF-α) has been implicated in multiple diseases including arthritis, psoriasis, sepsis, Crohn's disease, septic shock, tumour metastasis and abnormal wound healing. TNF-α converting enzyme (TACE) or ADAM 17 (A Disintegrin And Metalloprotease) is a member of a family of zinc metalloproteases, and is an important regulator of inflammation, immune regulation, and cellular proliferation as a consequence of its ability to catalyze the activation of TNF-α from a membrane bound to a soluble form.

Programme Profile

Using a structure-based design approach InhibOx has utilized its proprietary computational chemistry and drug discovery expertise to identify novel small molecule inhibitors of TACE with the following profile:

Potent inhibitors of TACE (low nanomolar IC50s)
Inhibit secretion of TNF-α from cells at nanomolar concentrations
Highly selective over enzymes of the MMP and ADAM families
Encouraging ADME profile (metabolic stability, phys. chem. properties)

These TACE inhibitors are of potential utility as new therapeutic agents against chronic inflammatory and other diseases that are mediated by TNF-α. Further optimization, with the aim of identifying clinical candidates, is ongoing.

Malaria

Malaria remains a very significant world health problem. The malaria parasite spends part of its life inside a host red blood cell. Leaving the cell to continue its life-cycle requires a protease activity, so the enzymes involved have potential as anti-malarial drug targets. In collaboration with Prof. Mike Blackman of the MRC, a virtual screen for lead compounds against one of these proteases, PfSUB1, has been performed and active compounds have been identified.

Nuclear Hormone Receptors

Nuclear hormone receptors (NHRs) consists of a family of DNA binding transcription factors whose function can be controlled by small molecules and represents one of the most important classes of drug targets. The superfamily includes receptors for hydrophobic molecules such as steroid hormones such as estrogens, glucocorticoids, progesterone, mineralocorticoids and androgens.

Identification of specific NHR modulators, as well as identification of ligands for orphan NHRs, will lead to new therapies for many human diseases. There is considerable commercial interest in NHRs, with pharmaceutical companies investing significantly in NHR-targeted drugs, which are estimated to be 10-15% of the $400 billion global pharmaceutical market. Through a targeted virtual screening programme we have identified novel, non-steroidal NHR modulators with the potential to be developed into series with novel selectivity profiles.