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Clinical candidate from PKB/AKT collaboration with Astex selected by AstraZeneca

Astex Therapeutics announced recently that AstraZeneca has selected a clinical candidate from the PKB inhibitor collaborative programme.

The programme began in 2003 through Astex’s collaboration with The Institute of Cancer Research (ICR) and Cancer Research Technology Limited (CRT). AstraZeneca’s collaboration with Astex on the drug discovery programme began in 2005. The selection of a promising clinical candidate triggers a milestone payment and Astex, the ICR and CRT are eligible to receive further milestones and royalties during clinical development and commercialization of the candidate. AstraZeneca will be responsible for progressing the clinical candidate through clinical development and into the market.

Protein kinase B (PKB, also known as Akt) is one of the most exciting new molecular targets for the treatment of cancer, and is a key enzyme in the mTOR/PI3K/PKB tumour cell survival pathway, dysregulation of which is implicated in the emergence of resistance of certain cancers to many commonly used anti-cancer drugs.

This new clinical candidate is the second PKB inhibitor to be selected based on research carried out under the original agreement between Astex, ICR and CRT. AT13148, a PKB inhibitor identified from a chemical series that is distinct from the series that led to the new AstraZeneca candidate, is in preclinical development under the Clinical Development Partnerships programme of Cancer Research UK. Astex retains worldwide exclusive rights to AT13148.

Les Hughes, Vice President of AstraZeneca’s Cancer Research Area said: ‘AstraZeneca is committed to the research and development of new, targeted anti-cancer therapies. We are delighted to add this new clinical candidate to the number we already have in development and look forward to seeing the results of key studies in the coming years.’

Professor Paul Workman, Director of the Cancer Research UK Centre for Cancer Therapeutics at the ICR, added: ‘Scientists at The Institute of Cancer Research have been studying the PKB pathway for many years, as it is known to be important in tumour development, and were the first to determine the crystal structure of the PKB enzyme. We believe that PKB inhibitors could potentially block the growth of a wide range of cancers and are very pleased that AstraZeneca’s decision to take this compound forward to clinical trials means that patients could soon benefit from this exciting new approach.’

Dr Phil L’Huillier, CRT’s Director of Business Management said: ‘This deal builds on a very successful collaboration between the academic and industrial sectors. It is pleasing to see, and important that the drug is being taken forward to establish if it might help to treat cancer patients.’

PKB/Akt is an important component of one of the best-understood tumour survival pathways and one that is frequently activated in tumours as a result of disruption of the tumour suppressor PTEN. PKB/Akt is a protein ser/thr kinase that is activated by many growth factors and has key roles in both the growth and the survival of many tumours, as well as being implicated in resistance of tumours to chemotherapy.

Recently, it has become clear that resistance to many therapeutic agents – as seen, for example, with EGFR kinase inhibitors and with cytotoxics such as doxorubicin and cisplatin – is associated with an upregulation of PKB activity by one of the above mechanisms. Thus, inhibitors of PKB have potential both in monotherapy and in combination with existing therapies.

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