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Martin Edwards Showcases Company's Innovative Drug Design Processes
 

Martin Edwards Showcases Company's Innovative Drug Design Processes
Crystal structure of crizotinib binding to ALK and cMet

Worldwide Medicinal Chemistry's (WWMC) innovative use of structure-based drug design (SBDD) and physical properties-based optimization (PPBO) helps Pfizer deliver on the pipeline by allowing chemists to analyze complex data and view computational models of the compounds they are designing and synthesizing. These groundbreaking processes, led by Martin Edwards, Vice President and Head of R&D Cancer Chemistry in La Jolla, ultimately enable the design of better and more potent molecules, giving Pfizer a competitive market edge.

Martin Edwards spoke about the SBDD and PPBO processes at the 5th Drug Design and Medicinal Chemistry Conference last month in San Diego, where over 125 leading industrial and academic experts gathered to share news of their latest projects and research. He has been invited to speak again and hold a workshop on both processes in San Francisco in February. So what is it about SBDD and PPBO that has caused the industry to take notice?

"This is quite different from what other medicinal chemists at other companies are doing," said Edwards. "PPBO is a unique way of thinking about how to understand very complex data on large numbers of compounds by using multi-dimensional graphs to extract knowledge that would be hidden to a lot of people if they looked at that data in traditional ways."

Chemists traditionally study numerous tables of data on molecular compounds, which eventually yield the results they need to build a drug. PPBO produces graphical representations of large numbers of compounds and large numbers of data at the same time, giving Pfizerýs chemists the ability to spot what they need in order to design the clinical parameters of a drug more rapidly, as well as design more robust compounds that will survive to go to market. The PPBO approach is further enhanced by SBDD, and both processes work best when integrated.

"SBDD is all about designing using computational visualizations or models, derived from x-ray protein crystal structures of compounds that are actually bound to the target that we're targeting. SBDD allows us to design improved compounds because we have a much better understanding of how compounds are interacting with our target protein," said Edwards. "When using SBDD, we can apply the design principles of PPBO in a much more intelligent and targeted manner because of our knowledge of the compound protein interactions. WWMC teams are fortunate to benefit from some amazing structural biology that is essential for generating and understanding the protein structural data and visualizations required as a platform for SBDD."

Role in Pfizer's Cancer Medicines

Edwards' keynote presentation at the conference highlighted SBDD and PPBO's role in the invention of axitinib and Xalkori (crizotinib), two cancer medicines submitted to the FDA for approval in 2011. Xalkori is the first and only oral anaplastic lymphoma kinase (ALK) inhibitor approved by the U.S. Federal Drug Administration (FDA) for the treatment of the three to five percent of advanced non-small cell lung cancer (NSCLC) patients who test positive for an ALK gene rearrangement. Xalkori was approved just four years after publication of the discovery of the ALK fusion gene in NSCLC — an "unprecedented industry timeframe" said Edwards.

"With Xalkori, we wouldn't have progressed to the compound leads we had without SBDD and PPBO," said Edwards. "The target that we were attacking is a very difficult one to inhibit. SBDD and PPBO helped us get a better look at Xalkori's crystal structure and allowed us to come up with very robust molecules in terms of all of the properties needed to get all the way to market and survive."

With WWMC widely adopting the SBDD and PPBO approaches, it's clear that both processes are becoming key fundamental platforms of innovative drug design, further solidifying Horizon 1 of WRD's Three Horizon Strategy: delivering the portfolio by maintaining and enhancing world-leading small molecule design capability.

"I think SBDD and PPBO will increasingly become part of industry-wide drug design," said Edwards. "But our job at Pfizer right now is to make sure we can stay competitive, add a new wrinkle to the traditional process, and successfully bring new drugs to market on behalf of the patient."

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