Astex reveals structure of key drug metabolizing enzyme - cytochrome P450 3A4 - in Science

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Astex reveals structure of key drug metabolizing enzyme - cytochrome P450

3A4 - in Science

 

Cambridge, UK, July 16 2004.

 

 

 

Cambridge, UK, 16th July 2004 - Astex Technology, the fragment-based drug

discovery and development company, today announced that its scientists

had published the 3-dimensional structure of human cytochrome P450 3A4,

the most important drug metabolising enzyme. The crystal structure of the

protein is reported in the leading science journal Science1. This is the

first time this structure has been published and follows another world

first when Astex published in Nature2 the first 3-dimensional crystal

structure of a human cytochrome P450 protein, CYP450 2C9. CYP450 3A4 is

one of four key enzymes that are responsible for metabolizing more than

90% of drugs and cause significant attrition in the drug development

process.

“We are delighted that we have published the crystal structure of human

CYP450 3A4,” said Dr Harren Jhoti, Astex’s Co-Founder and Chief

Scientific Officer. “These proteins are membrane-associated, complex

structures and so represent a major challenge for structural biology.

This is the second human cytochrome P450 structure we have solved, the

first being human CYP450 2C9, reflecting our significant achievements in

this important area of drug discovery. By exploring how these cytochrome

P450s recognise drug molecules at the atomic level, we will be able to

design rationally drugs with better metabolic and toxicity profiles and

thus an improved chance of being commercialized.”

CYP450 3A4 is generally regarded as the most important family member of

these drug metabolising enzymes; it is estimated that as many as 50% of

all known drugs interact with this form of cytochrome P450. However,

CYP450 3A4 is also the most poorly understood member with respect to its

drug metabolising action and represents a major problem in drug

development. Astex’s proprietary P450 structural information enables the

company and its collaborators to generate lead compounds with optimal

drug metabolism and pharmacokinetic properties and so reduce attrition

rates in drug development.

Astex has research agreements with AstraZeneca, Aventis, Fujisawa and

Mitsubishi Pharma focused on solving and utilising novel cytochrome P450

crystal structures.

1. Pamela A. Williams, Jose Cosme, Dijana Matak Vinkovic, Alison Ward,

Hayley C. Angove, Philip J. Day, Clemens Vonrhein, Ian J. Tickle and

Harren Jhoti. “Crystal structures of human cytochrome P450 3A4 bound to

metyrapone and progesterone.” 15 July 2004 published online at

www.sciencexpress.org; 10.1126/science.1099736

2. Pamela A. Williams, Jose Cosme, Alison Ward, Hayley C. Angove, Dijana

Matak Vinkovic and Harren Jhoti. ‘Crystal structure of human cytochrome

P450 2C9 with bound warfarin.’ Nature, 2003 Jul 24;424(6947):464-8

Notes to Editors

Cytochrome P450s are the most significant group of drug-metabolising

enzymes in humans. The action of these proteins is the cause of adverse

reactions to many marketed drugs and drug-combination therapies. In

addition, many failures in drug development have been attributed to this

class of proteins; drugs may be metabolized too rapidly before they have

a chance to be effective, or they may be broken down into smaller

molecules which may be toxic, or they can even interfere with the

activity of CYP450s so that other drugs given at the same time cause side

effects or become dangerous. The insight provided by the crystal

structure of cytochrome P450s aims to improve the success rates and

economics of drug development and result in safer and more effective new

medicines.

The purpose of drug metabolism is to make the drugs more water-soluble so

that they can be easily excreted from the body after their desired effect

has been exerted. Four human cytochrome P450s (CYP 2C9, CYP 2C19, CYP 2D6

and CYP 3A4) account for the metabolism of nearly all clinically useful

medications. Astex has targeted 10 CYP450 proteins including seven human

isoforms and three further mammalian isoforms in a major program of P450

structural biology research. Knowledge of the specific ways drugs bind to

CYP450s can be exploited by Astex in novel strategies for drug design to

modulate their potential for binding CYP450, while retaining compound

potency and selectivity.

In addition to Astex’s research agreements with pharmaceutical companies,

Astex collaborates with world-leading experts in X-ray crystallography

such as Global Phasing (Cambridge, UK), whose novel methodology has

enabled significant breakthroughs in Astex’s cytochrome P450 program.

Glossary

Pharmacokinetics looks at the action of drugs in the body, including the

processes of absorption, transformation, distribution to tissues,

duration of action and elimination.

About Astex

Astex is a 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, the first of which will

enter clinical trials in 2005.

Astex’s leading position in fragment-based drug discovery derives from

its integrated discovery engine, Pyramid. High-throughput X-ray

crystallography is used to identify drug fragments bound to target

proteins and to transform the fragments, using efficient medicinal

chemistry, into potent, selective lead compounds. Pyramidhas 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 alliances with major pharmaceutical companies including

AstraZeneca, Aventis, Boehringer Ingelheim, Mitsubishi Pharma and

Schering AG. Astex 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 about Astex please visit the Company’s website at

www.astex-technology.com.

 

 

 

 

 

 

 

 

 

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