InhibOx is pursuing several drug discovery programmes, either fully internal funded, or in
collaboration. These include:
ERR-alpha
Recently it has been discovered that (ERR-a) (NR3B1) plays a critical role in controlling energy expenditure.
(ERR-a) k.o. mice show an "athletic" lean phenotype which can be at least partially explained by ERR-a interacting with PGC-1,
a cofactor known for regulating energy metabolism in fat and muscle tissues. Moreover, a direct involvement of ERR-a,
together with PGC-1 could be demonstrated for the induction of so-called OXPHOS genes, i.e. for genes that lead to
mitochondrial biogenesis and induction of oxidative phosphorylation metabolism. Stimulation of the (ERR-a) / PGC-1 couple
in skeletal muscle leads to a switch from glucose consuming fast twitch ("white") muscle fibers towards oxidative metabolism-based
slow twitch ("red") fibers. Thus it appears as if (ERR-a) shifts the balance from glucose consumption towards fatty acid burning in
cardiac and skeletal muscle. With this effect, (ERR-a) shows a good profile as a target for an anti-obesity / metabolic syndrome drug.
InhibOx is collaborating with Phenex, in progressing its hit series, which was identified out of its proprietary screening collection,
that selectively modulate the activity of ERR-a, and in identifying new hit series.
Tumour Necrosis Factor alpha Converting Enzyme (TACE)
Tumour necrosis factor alpha (TNF-a) is a well validated therapeutic target for the treatment of rheumatoid arthritis and is implicated in a
number of other inflammatory disease processes. Biological anti-TNF therapies are showing success in a clinical setting. However, as with many biological agents,
issues of cost and delivery mean that a small molecule therapy would be highly advantageous. TACE is an enzyme that is involved in the generation of the active form of (TNF-a) from an inactive precursor.
TACE inhibitors have the potential to prevent the secretion of the soluble, mature, (TNF-a) and may therefore be effective in treating rhematoid arthritis and other diseases in which it is implicated, such as Crohn's disease or psoriasis.
In a highly successful optimization programme, InhibOx has, starting from micromolar leads, identified novel series of TACE inhibitors with sub-nanomolar potency.
Further optimization, with the aim of identifying pre-clinical candidates, is ongoing.
