Astex Presents Updates on AT13387, its HSP90 Inhibitor, and AT9283, its Multi-Targeted Kinase Inhibitor at the EORTC-NCI-AACR Cancer Conference

Cambridge, UK 14th October, 2008. Astex Therapeutics Limited, the world’s leading fragment-based drug discovery company, today announced that it is to present key findings on two of its wholly owned clinical stage anti-cancer compounds and on one of its earlier stage drug discovery programmes at the 20th EORTC-NCI-AACR1 symposium on “Molecular Targets and Cancer Therapeutics” to be held in Geneva, Switzerland, 21-24 October 2008.

Astex’s scientists will present further data on AT13387, the Company’s novel small molecule inhibitor of heat shock protein 90 (HSP90). AT13387, which has options for oral delivery, is currently being administered as an intravenous formulation in a Phase I study in cancer patients with solid tumours at three leading cancer centres in the USA. AT13387 is the third product derived from Astex’s PyramidTM fragment chemistry platform to enter human clinical trials.

Astex will also present the first disclosure of the full chemical structure of AT9283, its multi-targeted kinase inhibitor. AT9283 is currently being tested in multiple Phase I and Phase I/IIa human clinical trials for the treatment of a variety of solid tumours and haematological malignancies. Early evidence of clinical activity has been observed in patients treated with AT9283.

The Company will also present data on its selective JAK2 inhibitor programme, which is targeting the treatment of a number of myeloproliferative diseases. The selective JAK2 inhibitor programme is designed to complement the JAK2 inhibitory activity already observed in myelofibrosis patients treated with AT9283.

1European Organisation for Research and Treatment of Cancer - National Cancer Institute - American Association for Cancer Research



Jeremy Carmichael, PhD Director of Business Development

Astex Therapeutics Ltd 436 Cambridge Science Park Milton Road, Cambridge CB4 0QA, UK

Tel: +44(0)1223 226289 Fax: +44(0)1223 226201

Editor's Notes

Poster Title: AT13387, A Fragment Derived Clinical Candidate is Active in Lung and Melanoma Models Session Date: Wednesday 22nd October, 2008, 12:00-14:15 Session ID: Poster Session: Heat shock proteins. Abstract Number: 147

Poster Title: Fragment-based discovery of AT9283; a multi-targeted kinase inhibitor with potent Aurora kinase activity Session Date: Thursday 23rd October, 2008, 12:00-15:00. Session ID: Poster Session: Aurora kinase. Abstract Number: 287

Poster Title: Identification of potent, selective JAK2 inhibitors using a fragment-based screening approach Session Date: Friday 24th October, 2008, 12:00-14:00 Session ID: Poster Session: Signal Transduction Modulators. Abstract Number: 573

Poster Abstracts:

i) AT13387, A Fragment Derived Clinical Candidate is Active in Lung and Melanoma Models

HSP90 is involved in the folding, maturation and stabilisation of key signalling molecules involved in cell proliferation, survival and transformation. Inhibition of HSP90 can, therefore, simultaneously affect multiple signalling pathways required to maintain cellular transformation and as such is an attractive target for anti-cancer drug design. Recently, HSP90 inhibition has been found to be of benefit in pre-clinical models of lung cancer and melanoma that depend on EGFR mutations, MET amplification and B-RAF mutations.

Astex Therapeutics has applied its fragment-based screening approach (Pyramid™) which employs a range of biophysical techniques, including X-ray crystallography and NMR (nuclear magnetic resonance) spectroscopy, followed by structure based drug design to discover AT13387. This compound has now been progressed into phase I clinical trials. AT13387 has prolonged tumour pharmacokinetics and pharmacodynamics in tumour models.

The effects of AT13387 have been investigated in several model systems including lung and melanoma models that have proved to be particularly sensitive to the agent. NCI-H1975 and A549 non small cell lung cancer and SKMel-28 and A375 melanoma cell lines have been characterised in detail for their sensitivity to AT13387. In a more extensive 100 cell line panel screen multiple small cell lung cancer and non small cell lung cancer lines proved to be the most sensitive to AT13387. Both the NCI-H1975 (non small lung cancer) and the A375 (melanoma) xenograft models were demonstrated to be sensitive to single agent activity of AT13387 with concomitant modulation of pharmacodynamic markers. Furthermore, standard of care chemotherapies for both diseases in combination, in vitro and in vivo were tested against lung and melanoma models successfully.

ii) Fragment-based discovery of AT9283; a multi-targeted kinase inhibitor with potent Aurora kinase activity

Today there is widespread acceptance that chemical fragments can be progressed into nanomolar (nM) lead series and on into clinical candidates. In the field of oncology there are a number of compounds, currently undergoing clinical evaluation, which can be attributed to a fragment-based approach. Examples include AT7519 (CDK inhibitor), ABT-263 (Bcl-XL inhibitor), AT13387 and NVP-AUY922 (both HSP90 inhibitors). Here we describe the fragment-based discovery of AT9283, a multi targeted kinase inhibitor with potent Aurora kinase activity, which is currently in clinical trials.

In this work, a low molecular weight heterocyclic fragment provided the starting point for a structure-based medicinal chemistry programme. Typically, a detailed structural understanding of the binding interactions between the fragment and its target protein is required to pursue a fragment-based approach. In this case, X-ray crystallographic structures were generated using a novel soakable form of Aurora A and were used to drive the optimisation towards potent (< 10 nM) dual Aurora A / Aurora B inhibitors. These compounds inhibited growth and survival in HCT116 cells and produced the polyploid cellular phenotype typically associated with Aurora kinase inhibition. Optimisation of cellular activity and physicochemical properties ultimately led to the identification of AT9283. In addition to Aurora A and Aurora B, AT9283 was also found to inhibit a number of other kinases including JAK2, Flt3 and Abl T315I (< 10 nM). AT9283 demonstrated excellent in vivo efficacy in mouse xenograft models and was selected for pre-clinical development.

In conclusion, low molecular weight fragments provide good chemical starting points for the discovery of drug candidates. During this programme, structure-based optimisation of a heterocyclic fragment led to the identification of AT9283 which is currently in Phase I clinical trials for the treatment of cancer.

The structure of AT9283 will be fully disclosed at the meeting.

iii) Identification of potent, selective JAK2 inhibitors using a fragment-based screening approach

Janus Kinase 2 (JAK2) has become a key target in myeloproliferative diseases since the discovery of the activating JAK2V617F mutation in a significant proportion of these patients. This mutation, and others subsequently discovered, induces cytokine-independent proliferation of cells that express erythropoietin receptors. This causes these cells to become hypersensitive to cytokines and to upregulate the phosphorylation of Signal Transducer and Activator of Transcription (STAT) 5 and signalling through this pathway.

We used our fragment-based screening approach, Pyramid™, to identify multiple low molecular weight fragments that bound to the kinase domain of JAK2. These weakly binding hits were then optimised into potent lead compounds against the target using a structure-guided approach.

Lead compounds were identified with sub-10 nM potency against the isolated JAK2 enzyme and were also shown to have sub-micromolar cellular activity in a number of JAK2-based cellular assays. Compounds inhibited proliferation of an engineered JAK2-dependent Ba/F3 cell line. They also inhibited the phosphorylation of the JAK2 substrate STAT5 and other downstream markers in Human erythroleukemia (HEL) cells at similar concentrations, indicating the mechanism of cellular action was through JAK2 inhibition.

These JAK2 inhibitors were less active against a number of other isolated kinases, including other members of the JAK family, JAK1, JAK3 and Tyk2. Optimised lead compounds were 50 and 100-fold selective for JAK2 over JAK3 and JAK1 enzymes respectively. The selectivity for JAK2 over JAK3 seen in the isolated enzyme system translated into cells with the proliferation of a JAK2-driven Ba/F3 cell line being inhibited at least 17 times more potently than that of a JAK3-driven Ba/F3 line by one of our lead compounds.

Overall we have successfully used a fragment-based screening approach to identify potent and selective JAK2 inhibitors, both against isolated enzymes and in cellular systems, which merit further optimisation.

Astex Therapeutics

Astex is a UK-based biotechnology company that discovers and develops novel small molecule therapeutics. Using its pioneering fragment-based drug discovery platform Pyramid™, Astex has built a pipeline of five molecularly-targeted oncology drugs, of which three are currently being tested in clinical trials and two are in pre-clinical development.

In addition to its proprietary research programmes, Astex’s productivity in lead discovery has been endorsed through numerous partnerships with major pharmaceutical companies, including AstraZeneca, Bayer-Schering, Boehringer Ingelheim, Novartis and Johnson and Johnson.

For further information on Astex please visit the Company’s website at



Posted: October 2008

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