Projects
PI3Kγ is a dual lipid-protein kinase, which represents one of four isoforms of class I phosphat- idylinositol-3-Kinases. PI3Kγ acts mainly downstream of G-Protein Coupled Receptors and is a key mediator of directed movement of immune cells towards chemoattractants. It is also involved in other immune processes, such as mast cell degranulation and T-cell development. Inhibition of the lipid kinase activity of PI3Kγ, both genetically and with tool compounds, has been shown to have a beneficial effect in models of disease, like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or inflammatory bowel disease (IBD).
Mutations in the LRRK2 (leucine-rich repeat kinase 2) gene are a common cause of both familial and sporadic Parkinson's Disease. The majority of these mutations increase the kinase activity of LRRK2. The protein itself is extremely large and has a number of domains that modulate kinase activity. This complexity presents difficulties to traditional biochemical screening approaches. Using a version of Kinobeads™ tailored to LRRK2, Cellzome has identified three lead series, one of which has been optimised to yield potent, selective inhibitors of LRRK2 activity.
The mammalian target of rapamycin, commonly known as mTOR, is a large serine/threonine protein kinase that regulates cell growth, proliferation and survival by impacting on protein synthesis and transcription. The inhibition of mTor by rapamycin causes immunosuppression, and more recently clinical studies of a rapamycin analogue have revealed beneficial effects in rheumatoid arthritis. These findings suggest mTor is an attractive drug target not only for the suppression of transplant rejection, but also for inflammatory diseases.
ZAP-70 (Zeta-associated protein of 70 kilodalton) is a member of the protein tyrosine-kinase class of drug targets. ZAP-70 acts downstream of the T-cell receptor. The potential of ZAP-70 as a target for anti-inflammatory therapies has been known for a long time, but it has proven difficult to develop potent drug-like inhibitors. Using Kinobeads™, Cellzome has identified a physiologically relevant form of ZAP-70 in T-cells, which is accessible to small molecule screening.
Janus kinase 3 (JAK3) is a cytoplasmic protein tyrosine kinase that associates with various cytokine receptors. JAK3 plays a key role in the response of immune cells to cytokines, especially in mast cells, lymphocytes and macrophages. Inhibition of JAK3 has shown beneficial clinical effects in rheumatoid arthritis and transplant rejection. Even though some JAK3 inhibitors have been reported to be selective in vitro over the closely related kinases JAK1, JAK2 and TYK2, this selectivity translated poorly into the cellular setting.
Epigenetic targets
During inflammation, epigenetic mechanisms play a key role in controlling immune cell differentiation and inflammatory gene expression. One major epigenetic mechanism is the specific enzymatic modifica- tion of histone tails, which affects the packaging of DNA into chromatin and through that controls the transcription of specific genes. Enzymes, such as histone deacetylases (HDAC) or methyltransferases (HMT) can change the modification of the histone tails and therefore change the 'histone code'. Cellzome has developed a novel epigenetics drug discovery platform, Episphere™, to target these enzymes in their native, disease-relevant environment.