Astex Therapeutics Initiates Clinical Trial With Investigational Anti-Cancer Drug AT9283

Posted by rob on September 26, 2006 under Uncategorized | Be the First to Comment

CAMBRIDGE, England, Sept. 26 /PRNewswire/ — Astex Therapeutics today announced that it had begun dosing first patients in a Phase I/IIa clinical trial of its investigational anti-cancer drug AT9283. Astex discovered AT9283, a potent inhibitor of Aurora kinases, using its innovative fragment-based drug discovery technology, Pyramid(TM).

This is Astex’s second product to enter clinical development. The company’s lead product, AT7519, is already in a Phase I trial at sites in the US and the UK. This initial clinical trial of AT9283 is designed to assess safety and tolerability and may provide preliminary evidence of efficacy in patients with haematological malignancies. It is being conducted at the University of Texas MD Anderson Cancer Center, one of the world’s leading oncology centres. Astex plans to initiate additional clinical studies of AT9283 in North America and Europe within the next six months.

In addition to its inhibition of Aurora kinases, AT9283 is highly active against the Gleevec(R) resistant T315I abl mutation and could benefit patients who have failed treatment with agents such as Gleevec(R) and Sprycel(TM). AT9283 is also a potent inhibitor of JAK-2 and the present trial will assess its activity in patients with myeloproliferative disorders associated with activating mutations of this protein.

“We are delighted to have initiated this trial in collaboration with Dr Hagop Kantarjian, a leading expert in the field of leukaemia,” said Leon Bushara, Chief Executive Officer of Astex. “Astex has moved two products into clinical development within twelve months, underscoring the unique productivity of our R&D effort. Our objective is to advance at least one new product into clinical trials every year.”

“Targeted agents like the Aurora kinase inhibitor AT9283 have already shown evidence of clinical efficacy in the treatment of patients with haematological malignancies, such as Chronic Myelogenous Leukaemia (CML). I am very pleased to be involved in trialling this novel agent which could be of significant benefit to cancer patients,” said Dr Hagop Kantarjian, Professor of Medicine and Chairman of the Department of Leukemia at University of Texas MD Anderson Cancer Center.

Editor’s notes: AT9283: Aurora kinase inhibitor

AT9283 is an inhibitor of mitosis (cell division) and is the second most advanced product in the Astex portfolio. AT9283 is a potent inhibitor of the Aurora A and B kinases and has been shown to arrest tumour growth in a range of tumour models. Aurora kinases play a key role in mitotic checkpoint control in cell division. Both Aurora A and B are over-expressed in many human tumours and are believed to be excellent targets for anti-cancer therapy.

The clinical study currently underway at MD Anderson is entitled “A Phase I/IIa Open-label Study to Assess the Safety, Tolerability and Preliminary Efficacy of AT9283, a Small Molecule Inhibitor of Aurora Kinases, in Patients with Relapsed or Refractory Acute Leukaemias, Chronic Myeloid Leukaemia or High-Risk Myelodysplastic Syndromes.”

About Astex Therapeutics

Astex Therapeutics is a UK-based biotechnology company producing novel small molecule therapeutics. Using its pioneering fragment-based drug discovery approach, Astex has rapidly established a broad pipeline of next- generation, molecularly-targeted oncology drugs. Astex’s lead compound, AT7519, is currently in Phase I clinical trials in the US and in the UK. The Company’s second clinical-stage compound, AT9283 is an Aurora kinase inhibitor currently in a Phase I/IIa clinical study in the US. The Company has two further clinical candidates; AT9311, an oral cell cycle inhibitor and AT13387, an Hsp90 inhibitor, both of which are in formal pre-clinical development. All four of Astex’s current drug products have been discovered internally using the Company’s proprietary drug discovery approach.

Astex’s leading position in fragment-based drug discovery derives from its integrated discovery engine, Pyramid(TM). High-throughput X-ray crystallography and other biophysical techniques are used to identify drug fragments bound to target proteins and to transform the fragments, using efficient medicinal chemistry, into potent, selective drug candidates. Pyramid(TM) has been successfully applied across a wide variety of therapeutic targets, including those regarded as ‘intractable’ by the pharmaceutical industry, resulting in lead compounds for the potential treatment of cancer, inflammation and Alzheimer’s disease.

Astex’s unprecedented productivity in lead discovery has been endorsed by drug discovery and development alliances with major pharmaceutical companies including AstraZeneca, Astellas Pharma, Boehringer Ingelheim, Mitsubishi Pharma, Novartis, Sanofi-Aventis and Schering AG. These alliances have a total potential value in excess of US$1billion including the US$520m alliance signed with Novartis in December 2005 which is focused on the development of AT9311 and AT7519.

Astex Therapeutics was established in 1999 and is well financed by leading, blue chip US and European investors (Abingworth, Advent International, Alta Partners, Apax, GIMV, HypoVereinsbank, Oxford Bioscience Partners, Schering AG and the University of Cambridge).

For further information on Astex Therapeutics please visit the Company’s website at http://www.astex-therapeutics.com/

Hagop Kantarjian MD

Dr. Kantarjian is currently serving as Professor of Medicine and Chairman of the Department of Leukemia at University of Texas MD Anderson Cancer Center in Houston, USA, where he has been since joining as a fellow in the Department of Developmental Therapeutics in 1981. Hagop specializes in leukemia and holds an interest in creating new treatment approaches for these diseases. Hagop has authored and contributed to over 560 medical publications, articles and abstracts and, for his accomplishments, has received awards, including a Leukemia Society of America Scholarship from 1989-1994 and a Leukemia Society of America Special Fellow Scholarship from 1982-1983.

Gleevec(R) (imatinib mesylate) is a registered trademark of Novartis AG Sprycel(TM) (dasatinib) is a trademark of Bristol Myers Squibb Inc. Contacts Astex Therapeutics Leon Bushara Chief Executive Officer Tel +44 (0)1223 226200 Email: l.bushara@astex-therapeutics.com Web: http://www.astex-therapeutics.com/ Brunswick Group LLP Jon Coles / Justine McIlroy / Alex Tweed Tel. +44 (0) 207 404 5959 Email: astex@brunswickgroup.com

Astex Therapeutics

CONTACT: Leon Bushara, Chief Executive Officer of Astex Therapeutics,+44-1223-226200, l.bushara@astex-therapeutics.com; or Jon Coles, or JustineMcIlroy, or Alex Tweed, all of Brunswick Group LLP, +44-207-404-595,astex@brunswickgroup.com

Web site: http://www.astex-therapeutics.com/

Source: PRNewswire

 

Astex Therapeutics Initiates Clinical Trial With Investigational Anti-Cancer Drug AT9283

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A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation.

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A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation.

Prabhu S, Saadat D, Zhang M, Halbur L, Fruehauf JP, Ong ST.

1The Division of Hematology/Oncology, University of California, Irvine, CA, USA.

The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of protein synthesis, the mammalian target of rapamycin (mTOR), which suggests that dysregulated translation may also contribute to CML pathogenesis. In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation (inactivation) of 4E-BP1, an inhibitor of the eIF4E translation initiation factor. Experiments with rapamycin and the Bcr-Abl inhibitor, imatinib mesylate, in Bcr-Abl-expressing cell lines and primary CML cells indicated that Bcr-Abl and mTORC1 induced formation of the translation initiation complex, eIF4F. This was characterized by reduced 4E-BP1 binding and increased eIF4G binding to eIF4E, two events that lead to the assembly of eIF4F. One target transcript is cyclin D3, which is regulated in Bcr-Abl-expressing cells by both Bcr-Abl and mTORC1 in a translational manner. In addition, the combination of imatinib and rapamycin was found to act synergistically against committed CML progenitors from chronic and blast phase patients. These experiments establish a novel mechanism of action for Bcr-Abl, and they provide insights into the modes of action of imatinib mesylate and rapamycin in treatment of CML. They also suggest that aberrant cap-dependent mRNA translation may be a therapeutic target in Bcr-Abl-driven malignancies.Oncogene advance online publication, 28 August 2006; doi:10.1038/sj.onc.1209901.

PMID: 16936779 [PubMed - as supplied by publisher]

 

A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation.