Consortium of binding interactions

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

Ilene Schneider
BERLIN—A major problem in developingnew medicines is predicting whether or not a potential drug will beeffective in humans. To improve drug design by understanding howpotential drugs bind with their targets and by developing methods andtools to help researchers to study drug-target interactions, BayerHealthCare and Leiden University of the Netherlands are coordinatinga newly founded international consortium called "K4DD," orKinetics for Drug Discovery.

The five-year project will focus onoptimizing binding kinetics for drug candidates. The consortium,which is financially supported with $26 million by Europe'sInnovative Medicines Initiative (IMI), is "an excellent example ofa project in which public-private partnerships enable a collaborativeresearch 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 oflead discovery at Bayer HealthCare Global Drug Discovery, andcoordinator of the K4DD consortium.

The European Union and the Federationof Europe's Pharmaceutical Industries (EFPIA) work together in theBrussels-sponsored IMI. Last year, IMI issued a call to address thekinetics of the drug-target interaction. Laura Heitman and AdIjzerman, professor of medicinal chemistry at Leiden University, andfriends at the Vrije Universiteit Amsterdam started to form aconsortium of both academia and small businesses to address theissue. Applications were reviewed by external experts, selected byIMI Joint Undertaking (IMI JU), Müller-Fahrnow explains.

In December 2011, the consortiumwas chosen from 11 competing proposals. Seven EFPIA members joinedthe consortium to form the final K4DD consortium of 20 partners, ofwhich both Bayer and Leiden University are the leads. Otherinterested parties would need to go through a formal procedure tojoin the consortium. The official starting date was Nov. 1, and thekick-off meeting was Dec. 17 and 18, Ijzerman says.

K4DD has been launched to explore anovel concept in modern drug discovery, according to Müller-Fahrnow,who explains, "there is a clear understanding today that compoundbinding 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 ofthese drug-target interactions, mostly with respect to affinity andselectivity. However, despite the efforts in finding high-affinityand selective compounds, attrition rates of candidate drugs are stilldisappointingly high, and almost 90 percent of clinical drugcandidates that enter clinical trials still fail."

Ijzerman agrees that, "attritionalong the drug discovery pipeline is unacceptably high. The mainreason for that is lack of clinical efficacy in Phase II/III studies.Test-tube testing (a 'closed' system) may not reflect enough thein-vivo situation (an 'open' system). For instance, theemphasis on equilibrium studies in the test tube may not be verypredictive for an 'open' system, where there is littleequilibrium. Addressing the kinetic properties of the drug-targetinteraction may pay off more, as it adds another dimension to thecharacterization of that interaction."

The new five-year project will focus on"optimizing binding kinetics" for drug candidates and will workon the new concept of "target residence time" with the final goalof optimizing drug design, Müller-Fahrnow says. "Residence time"is the time a low-molecular weight (small) molecule remains bound toits target protein, and it may be of greater importance for itseffect in a patient than its affinity. The consortium was launched tooptimize the binding kinetics of each possible drug candidate in thefuture, i.e., define its "kinotype," next to its affinityand selectivity.

Consortium partners are "key playersin their fields" who "have been involved in the structureelucidation of drug targets, are at the forefront of bioanalyticaltechniques, are world leaders in pharmacology and bring the best ofcomputational resources for heavy computer calculations," accordingto Müller-Fahrnow.

"This ensemble of technologiesallows the study of the drug-target interaction from the very firstpicoseconds to the eventual times of treatment," he says.

"The responsibilities of the partnersare 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 ofdrugs, and tool compounds will be made. In the second work package,we will bring this knowledge to the design of better and more easilyaccessible techniques and robust off-the-shelf assays that can alsobe used outside the consortium. The few kinetic assays we currentlyhave are informative but tend to be very laborious, and this mustchange to increase awareness. The third work package aims totranslate the fundamental knowledge to in-vivo pharmacologyand physiology, even to include kinetic understanding into latepreclinical and clinical studies."

Müller-Fahrnow says that the goal ofthis project is that "kinetic aspects of drug-target interactionscan routinely be studied in robust and accessible assays for all maindrug target classes within and outside the consortium." He believesthat "kinotypic" knowledge should guide the identification andoptimization process of drug candidates in the early phases of drugdiscovery in the future. That means that drug development in generalshould be optimized by and benefit from the new consortium.

Ijzerman summarizes, "It is the firmambition of the consortium to instill long-lasting kinetic awarenessinto the scientific community. Eventually, it should become commonsense that kinetic parameters such as rate constants arecomplementary to the traditional parameters of affinity and potency.We think it should be self-evident by the end of the consortium'slifetime (2017) that editors and reviewers for scientific journalsroutinely ask for kinetic data, that industry adopts strategies tolearn about kinetics in the very early stages of the drug discoveryprocess and that these will help in a better prioritization of leadcompounds."


 

Ilene Schneider

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