Pyramid™ Discovery Platform

Integrated Platform, Innovative Solutions

Astex is recognized as a pioneer of fragment-based drug discovery (FBDD), an improved and more informed way of generating novel small molecule drugs, and one of the most significant advances in drug discovery in the past 25 years. In fact, Astex scientists were the first to coin the term FBDD in their landmark publication in 2002.

We employ Pyramid™, our proprietary fragment-based drug discovery platform, to rapidly deliver customized, high-quality drug leads with enhanced therapeutic potential across a wide variety of therapeutic targets and disease areas, including those regarded as “intractable” by the pharmaceutical industry.

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Advantages of fragment-based drug discovery

Designed to reduce attrition during drug development
Carefully monitors key characteristics such as ligand efficiency and in vivo activity during lead optimization
Ensures delivery of potent, selective and low molecular weight compounds with optimized drug metabolism and pharmacokinetic properties
Generates higher quality leads by optimizing key drug properties earlier in the process

How fragment-based drug discovery works

Conventional drug discovery and development, which relies heavily on high-throughput screening (HTS), has not delivered on its promise of increasing the numbers and quality of new drugs entering clinical trials. This is in part due to the complexity and the relatively large size of the compounds routinely being screened as well as the challenge of optimizing the hits derived from this approach.

Fragment-based drug discovery:

Starts with very small, low molecular weight drug fragments
These fragments have the potential to keep the overall complexity and molecular weight of each drug candidate low
These are key factors in successful drug development

Pyramid™ screening and rational drug design

Traditional bioassays used in HTS are generally unable to detect such small drug fragments because of their low potency binding to the protein target.

The Pyramid™ platform integrates a range of high-throughput biophysical techniques for screening such as X-ray crystallography, nuclear magnetic resonance spectroscopy, and calorimetry with fragment library design and computational methodologies. These are used to experimentally characterize in detail the interactions of very low molecular weight compounds (fragments) with their target proteins.

Unlike conventional screening techniques, the Pyramid™ process enables precise details of fragment binding to be routinely identified and visualized therefore allowing for rational molecule design.

Since 2016, Astex has invested heavily in the development of Cryo-electron microscopy (Cryo-EM) technology for fragment screening and to allow us to access drug discovery targets in additional target classes including membrane targets, ion channels and multi-target and multi-protein complexes.

Astex is a founder member of the Cambridge Pharmaceutical Cryo-EM Research Consortium which was established in 2016 to assist early-stage drug discovery research using Cryo-EM technology. Astex is developing Cryo-EM technology as a further biophysical technique to be used in FBDD.

Affords a detailed understanding of the fragment’s binding environment at an atomic level
These structural insights support a very efficient chemistry optimization process in which each additional functional group is designed to contribute to protein binding in a defined and productive manner
Drug candidates are designed to have lower molecular weight, reduced metabolic liability, improved target selectivity and ease of chemical synthesis