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Consortium of binding interactions
BERLIN—A major problem in developing new medicines is predicting whether or not a potential drug will be effective in humans. To improve drug design by understanding how potential drugs bind with their targets and by developing methods and tools to help researchers to study drug-target interactions, Bayer HealthCare and Leiden University of the Netherlands are coordinating a newly founded international consortium called "K4DD," or Kinetics for Drug Discovery.
The five-year project will focus on optimizing binding kinetics for drug candidates. The consortium, which is financially supported with $26 million by Europe's Innovative Medicines Initiative (IMI), is "an excellent example of a project in which public-private partnerships enable a collaborative research approach to tackle specific drug discovery problems of today and to come up with novel concepts in modern drug discovery," according to Dr. Anke Müller-Fahrnow, vice president and head of lead discovery at Bayer HealthCare Global Drug Discovery, and coordinator of the K4DD consortium.
The European Union and the Federation of Europe's Pharmaceutical Industries (EFPIA) work together in the Brussels-sponsored IMI. Last year, IMI issued a call to address the kinetics of the drug-target interaction. Laura Heitman and Ad Ijzerman, professor of medicinal chemistry at Leiden University, and friends at the Vrije Universiteit Amsterdam started to form a consortium of both academia and small businesses to address the issue. Applications were reviewed by external experts, selected by IMI Joint Undertaking (IMI JU), Müller-Fahrnow explains.
In December 2011, the consortium was chosen from 11 competing proposals. Seven EFPIA members joined the consortium to form the final K4DD consortium of 20 partners, of which both Bayer and Leiden University are the leads. Other interested parties would need to go through a formal procedure to join the consortium. The official starting date was Nov. 1, and the kick-off meeting was Dec. 17 and 18, Ijzerman says.
K4DD has been launched to explore a novel concept in modern drug discovery, according to Müller-Fahrnow, who explains, "there is a clear understanding today that compound binding characteristics to its molecular target (binding kinetics) are of high importance for eventual clinical drug efficacy. Therefore, drug discovery has also focused on the optimization of these drug-target interactions, mostly with respect to affinity and selectivity. However, despite the efforts in finding high-affinity and selective compounds, attrition rates of candidate drugs are still disappointingly high, and almost 90 percent of clinical drug candidates that enter clinical trials still fail."
Ijzerman agrees that, "attrition along the drug discovery pipeline is unacceptably high. The main reason for that is lack of clinical efficacy in Phase II/III studies. Test-tube testing (a 'closed' system) may not reflect enough the in-vivo situation (an 'open' system). For instance, the emphasis on equilibrium studies in the test tube may not be very predictive for an 'open' system, where there is little equilibrium. Addressing the kinetic properties of the drug-target interaction may pay off more, as it adds another dimension to the characterization of that interaction."
The new five-year project will focus on "optimizing binding kinetics" for drug candidates and will work on the new concept of "target residence time" with the final goal of optimizing drug design, Müller-Fahrnow says. "Residence time" is the time a low-molecular weight (small) molecule remains bound to its target protein, and it may be of greater importance for its effect in a patient than its affinity. The consortium was launched to optimize the binding kinetics of each possible drug candidate in the future, i.e., define its "kinotype," next to its affinity and selectivity.
Consortium partners are "key players in their fields" who "have been involved in the structure elucidation of drug targets, are at the forefront of bioanalytical techniques, are world leaders in pharmacology and bring the best of computational resources for heavy computer calculations," according to Müller-Fahrnow.
"This ensemble of technologies allows the study of the drug-target interaction from the very first picoseconds to the eventual times of treatment," he says.
"The responsibilities of the partners are along three work packages," Ijzerman explains. "In the first, we seek to understand the role of kinetics in drug discovery better. New techniques will be used to evaluate the binding kinetics of drugs, and tool compounds will be made. In the second work package, we will bring this knowledge to the design of better and more easily accessible techniques and robust off- the-shelf assays that can also be used outside the consortium. The few kinetic assays we currently have are informative but tend to be very laborious, and this must change to increase awareness. The third work package aims to translate the fundamental knowledge to in-vivo pharmacology and physiology, even to include kinetic understanding into late preclinical and clinical studies."
Müller-Fahrnow says that the goal of this project is that "kinetic aspects of drug-target interactions can routinely be studied in robust and accessible assays for all main drug target classes within and outside the consortium." He believes that "kinotypic" knowledge should guide the identification and optimization process of drug candidates in the early phases of drug discovery in the future. That means that drug development in general should be optimized by and benefit from the new consortium.
Ijzerman summarizes, "It is the firm ambition of the consortium to instill long-lasting kinetic awareness into the scientific community. Eventually, it should become common sense that kinetic parameters such as rate constants are complementary to the traditional parameters of affinity and potency. We think it should be self-evident by the end of the consortium's lifetime (2017) that editors and reviewers for scientific journals routinely ask for kinetic data, that industry adopts strategies to learn about kinetics in the very early stages of the drug discovery process and that these will help in a better prioritization of lead compounds."