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Rational drug design advances cancer treatments

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When it comes to developing potentially life-changing cancer drugs, rational drug design is a targeted approach that has led researchers to some amazing new discoveries, and could help lead the way for more in the future.

Rational drug design is such an effective concept because it picks a target that is essential to cancer cell survival, explained Robert Hromas, MD, FACP, professor and chair, Department of Medicine, College of Medicine, University of Florida & Shands, Gainesville. "It means to take a part of that protein that is essential for it to work, and to target small molecules to go into it and prevent it from functioning; therefore, the cancer cell can't divide," he said.

Using rational drug design means not just randomly dumping chemicals on a cancer cell, like the way most cancer drugs were developed prior to the last 10 years, Hromas added. "Most cancer drugs have been random testing of a number of different chemicals, but that approach has become bankrupt," he told ADVANCE. With advancements in medicinal chemistry and computational drug design, scientists can more precisely determine on the molecular level how to attack the cancer cell.

Even though rational drug design is being more widely used now as a streamlined process, it doesn't mean that the concept is not entirely new. "The concept has been around for years," said Stephen V. Frye, PhD, Fred Eshelman distinguished professor; director, Center for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina-Chapel Hill. "Each generation kind of redefines rational drug design, and there have been a number of different versions. There really aren't any other methods these days. There has always been a rationale for the way people have done drug discovery, we have just become more informed at the molecular level of targets in diseases, and oncology is the best example of this."

Advances in Drug Discovery
Using the rational drug design concept has been an improvement over past methods in a number of ways. One example is reducing the scale of effort when discovering which drug could work. "If you are randomly testing, you have to test hundreds of chemicals to find which one works," Hromas said. "Now the computer can spit out a molecular against the active side of your target protein that's going to work. There's a high chance that the computer can give you the molecules that would work the very first time. Now there's no need for banks of hundreds of thousands of mice and culture dishes."

Despite how more effective rational drug design is over randomized testing, that doesn't mean it is perfect. "One of the barriers with rational drug design is the fact that cancer cells are slippery and tricky," Hromas explained. "You target one protein, and lo and behold, two months later, cancer cells mutate and they get around that pathway easily."

Also, using rational drug design doesn't lessen the potential toxicity of the developed drug; that is something that cannot be changed. "Toxicity is usually manageable but can be an issue," Hromas said. "You are, unfortunately, stuck with the side effects you have. You can't change the molecular makeup and get rid of the side effect; you would lose the effectiveness of the molecule.

These drugs aren't perfect but there is an advantage," he continued. "Before using rational drug design, we had no drugs that worked for kidney and liver cancer. We're now able to kill cancers that before we had no treatment for."

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Rational Drug Design and Gleevec
The Novarits Oncology-developed drug Gleevec (imatinib mesylate) is one successful example of rational drug design. According to the company, Gleevec can be used to treat:

  • unresectable and/or metastatic malignant gastrointestinal stromal tumors (GST);
  • newly diagnosed adult and pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase;
  • relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia;
  • myelodysplastic/myeloproliferative diseases associated with platelet-derived growth factor receptor gene rearrangements;
  • aggressive systemic mastocytosis;
  • hypereosinophilic syndrome/chronic eosinophilic leukemia; and
  • unresectable, recurrent, and/or metastatic dermatofibrosarcoma protuberans.1

Gleevec, what Dr. Hromas has called the "poster child of rational drug design," was approved by the FDA in 2001. Its development goes all the way back to the 1960s.2 It has shown major benefits for those suffering, especially from CML and GST.

Amanda Koehler is a freelance writer.

References

  1. Novartis Oncology. Gleevec. Available at: www.gleevec.com/health-care-professional/index.jsp. Last accessed Mar. 20, 2013.
  2. Buchdunger E, Zimmerman J. The Story of Gleevec. Available at: www.innovation.org/index.cfm/StoriesofInnovation/InnovatorStories/The_Story_of_Gleevec. Last accessed Mar. 20, 2013.



     

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