Consortium of binding interactions

K4DD helps researchers to analyze kinetics to determine drug safety and efficacy early in the development process

Ilene Schneider
BERLIN, Germany—A major problem in developing new medicinesis predicting whether or not a potential drug will be effective in humans. Toimprove drug design by understanding how potential drugs bind with their targetand by developing methods and tools to help researchers to study drug-targetinteractions, Bayer HealthCare and Leiden University of the Netherlands arecoordinating a newly founded international consortium called "K4DD," orKinetics for Drug Discovery.
 
The five-year project will focus on optimizing bindingkinetics for drug candidates. The consortium, which is financially supportedwith $26 million by Europe's Innovative Medicines Initiative (IMI), is "anexcellent example of a project in which public-private partnerships enable acollaborative research approach to tackle specific drug discovery problems of todayand to come up with novel concepts in modern drug discovery," according to Dr.Anke Müller-Fahrnow, vice president and head of lead discovery at BayerHealthCare Global Drug Discovery, and coordinator of the K4DD consortium.
 
The European Union and the Federation of Europe'sPharmaceutical Industries (EFPIA) work together in the Brussels-sponsored IMI.Last year, IMI issued a call to address the kinetics of the drug-targetinteraction. Laura Heitman and Ad Ijzerman, professor of medicinal chemistry atLeiden University, and friends at the Vrije Universiteit Amsterdam started toform a consortium of both academia and small businesses to address the issue.Applications were reviewed by external experts, selected by IMI JointUndertaking (IMI JU), Müller-Fahrnow explains.

In December 2011, the consortium was chosen from 11 competing proposals.  Seven EFPIA members joined the consortium toform the final K4DD consortium of 20 partners, of which both Bayer and LeidenUniversity are the leads. Other interested parties would need to go through aformal 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 moderndrug discovery, according to Müller-Fahrnow, who explains, "there is a clearunderstanding today that compound binding characteristics to its moleculartarget (binding kinetics) are of high importance for eventual clinical drugefficacy. Therefore, drug discovery has also focused on the optimization ofthese drug-target interactions, mostly with respect to affinity andselectivity. However, despite the efforts in finding high-affinity andselective compounds, attrition rates of candidate drugs are stilldisappointingly high and almost 90 percent of clinical drug candidates thatenter clinical trials still fail."
 
Ijzerman agrees that, "attrition along the drug discoverypipeline is unacceptably high.  The mainreason for that is lack of clinical efficacy in Phase II/III studies. Test-tubetesting (a 'closed' system) may not reflect enough the in-vivo situation (an 'open' system). For instance, the emphasis onequilibrium studies in the test tube may not be very predictive for an 'open'system, where there is little equilibrium. Addressing the kinetic properties ofthe drug-target interaction may pay off more, as it adds another dimension tothe characterization of that interaction."
 
The new five-year project will focus on "optimizing bindingkinetics" for drug candidates and will work on the new concept of "targetresidence time" with the final goal of optimizing drug design, Müller-Fahrnowsays. "Residence time" is the time a low-molecular weight (small) moleculeremains bound to its target protein, and it may be of greater importance forits effect in a patient than its affinity. The consortium was launched tooptimize the binding kinetics of each possible drug candidate in the future, i.e., define its "kinotype," next to itsaffinity and selectivity.
 
Consortium partners are "key players in their fields" who"have been involved in the structure elucidation of drug targets, are at theforefront of bioanalytical techniques, are world leaders in pharmacology andbring the best of computational resources for heavy computer calculations,"according to Müller-Fahrnow.

"This ensemble of technologies allows the study of the drug-target interactionfrom the very first picoseconds to the eventual times of treatment," he says.
 
"The responsibilities of the partners are along three workpackages," Ijzerman explains. "In the first, we seek to understand the role ofkinetics in drug discovery better. New techniques will be used to evaluate thebinding kinetics of drugs, and tool compounds will be made. In the second workpackage, we will bring this knowledge to the design of better and more easilyaccessible techniques and robust off-the-shelf assays that can also be usedoutside the consortium. The few kinetic assays we currently have areinformative but tend to be very laborious, and this must change to increaseawareness. The third work package aims to translate the fundamental knowledgeto in-vivo pharmacology andphysiology, even to include kinetic understanding into late preclinical andclinical studies."
 
Müller-Fahrnow says that the goal of this project is that"kinetic aspects of drug-target interactions can routinely be studied in robustand accessible assays for all main drug target classes within and outside theconsortium." He believes that "kinotypic" knowledge should guide the identificationand optimization process of drug candidates in the early phases of drugdiscovery in the future. That means that drug development in general should beoptimized by and benefit from the new consortium.
 
Ijzerman summarizes, "It is the firm ambition of theconsortium to instill long-lasting kinetic awareness into the scientificcommunity. Eventually, it should become common sense that kinetic parameterssuch as rate constants are complementary to the traditional parameters ofaffinity and potency. We think it should be self-evident by the end of theconsortium's lifetime (2017) that editors and reviewers for scientific journalsroutinely ask for kinetic data, that industry adopts strategies to learn aboutkinetics in the very early stages of the drug discovery process and that thesewill help in a better prioritization of lead compounds."

Ilene Schneider

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