Discovery Programs
Astex's ongoing drug discovery programmes are focused on the discovery of novel molecularly-targeted drugs modulating protein targets in cell cycle and cell division control and oncogenic pathways including tumour survival pathways and growth factor pathways.
Cell Cycle and Cell Division C ontrol
Astex's current clinical candidates target the cell cycle and cell division control and, within drug discovery, Astex continues to target a range of proteins controlling these process including cyclin dependent kinases (CDKs), mitotic kinases such as aurora A and aurora B and transmembrane signalling through Janus Kinases (JAK).
CDKs are regulatory proteins of the eukaryotic cell cycle. They act, after association with a number of different cyclins throughout the progression of the cell cycle, as central mediators of cell division. Inhibition of CDKs could allow disruption of the cell cycle, evoking an anti-proliferative effect that may be useful as an intervention in the treatment of cancer and other diseases characterized by the rapid proliferation of cells. Astex's development products AT7519 and AT9311 target selected CDKs.
The aurora kinases are implicated in the onset and progression of many different human cancers. Aurora kinases play a key role in mitotic checkpoint control in cell division as cells progress through G2 and M phases of the cell cycle. Aurora A is associated with the centrosome and spindle during mitosis and abrogation delays entry into mitosis, while aurora B is associated with centromeres during prophase and abrogation disrupts cytokinesis and induces endoreduplication. Aurora A and B are over-expressed in many human tumours and as such represent promising targets for oncology drug discovery. Astex's development product AT9283 targets Aurora kinases
Oncogenic Pathways
Astex is also focusing drug discovery efforts on molecular targets in a number of oncogenic pathways where self sufficiency in growth signals promotes tumour cell growth.
JAK2 Inhibitors
JAK proteins are a family of trans-membrane signalling receptors which regulate the proliferation of individual members of the haematopoietic system. A single activating mutation in JAK2 has been shown to be of critical importance in the aetiology of a group of haematological disorders known as myeloproliferative syndromes (myelofibrosis with myeloid metaplasia, polycythaemia vera, and essential thrombocythemia). Astex's development product AT9283 inhibits signalling through both normal and mutated JAK2 receptors and represents a potentially novel approach to the treatment of these diseases.
FGFr Inhibitors
Fibroblast growth factor receptor (FGFr) is a receptor tyrosine kinase which activates the extracellular signal-regulated kinase / mitogen-activated protein kinase and the protein kinase B / Akt pathways which promote cell growth and survival. Amplification, over-expression or activating mutations of fibroblast growth factor receptor have been associated with bladder tumours, multiple myeloma, hormone-refractory prostate cancer, and breast cancer. Astex’s FGFr programme is directed towards the identification of selective inhibitors of FGFrs.
Ras/Raf Pathway
Dysregulation of the Ras/Raf/MEK/ERK pathway plays a major role in cancer pathogenesis and agents that target components of this pathway are proving to be important compounds for new cancer therapies. Astex has worked to identify novel potent inhibitors of the pathway in collaboration with the Wellcome Trust, Cancer Research Technology and the Institute of Cancer Research, and certain assets from this programme are continuing to be evaluated under a new collaboration between GlaxoSmithKline, The Wellcome Trust and the Institute of Cancer Research.
Survival Pathways
Akt/PKB Inhibitors
Astex has discovered multiple lead series and lead compounds against the target Akt/ PKB which regulates the survival pathway in cancer cells. Akt / PKB, part of the PI3Kinase pathway, is one of the most exciting new targets in the class of molecularly-targeted anti-cancer agents. The enzyme is a ser/thr kinase that is activated by many growth factors and plays a key role in both the growth and the survival of many tumours, as well as being implicated in resistance of certain tumours to chemotherapy.
Astex together with our collaborators in this area AstraZeneca, the Institute of Cancer Research and Cancer Research Technology is working to identify novel potent inhibitors of Akt/PKB. The programme is currently in advanced lead optimization with a view to identifying a first preclinical candidate during 2007.
HSP90
Heat-Shock Protein 90 (Hsp90) is a molecular "chaperone" that maintains the stability and functional shape of many oncogenic signalling proteins. Although an abundant protein, present in all cells, in tumour cells the ATPase is thought to exist as an activated, high-affinity form that differs from the form found in normal cells. Astex is exploiting this difference to develop selective inhibitors targeted at the tumour associated form as an important new class of anti-tumour agents. Astex’s development product AT13387 has been identified from this programme.