Chemical Biology Consortium - National Cancer Institute

National Cancer InstituteChemical BiologyConsortiumAccelerating the discoveryand development of newanticancer agentsU.S. DEPARTMENTOF HEALTH ANDHUMAN SERVICESNational Institutesof Health

NNO NH 2NH 3 COHHOH 3 CCH 3N N NCH 3NCH 3NH 2H 3 CCH 3NHNNNOOOHThe NCI’s Drug Discovery H 3 COand Development O Program Ois renowned for OHits success in OtakingOH Olate-stageOpreclinical drug candidatesOthrough the final steps of development to first-inhumanstudies. To advance the NCI’s mission of Obringing novel therapies to patients, and tofully exploit NCI’s expertise in the later stage of preclinical development, the Institute is nowfocusing O efforts and resources on Odrug candidate identification and optimization to enhancethe entry of early-stage drug candidates into the NCI therapeutics pipeline.OCHOThere is an undisputed need for shorter drug development timelines, enhanced molecularlytargeted drug discovery, O and more O streamlined HO processes to assess anticancer drug action—safety, efficacy, and the HOmechanism of HO action in vivo—early in the drug development cycle,as well as a mechanism to provide a rigorous, more effective, scientific basis for selectingpotential Oindications for new OH OO oncologic drugs. Recognizing this need, the NCI is adopting anew strategic approach that focuses on identifing novel molecular O targets and new moleculesthat interrogate those targets to support the construction Nof an enhanced and robust drugdiscovery and development O pipeline. HN NThis initiative is the new NCI-supported Cl Chemical Biology Consortium; Cl its goals are toaccelerate the discovery and development of effective first-in-class targeted therapies by Oproviding the proper environment to incubate new Odiscoveries and facilitate their growthinto full-scale oncologic drug development projects.OCH 3OOOHNOHCH 3OO NH 2H 3 CONOHNOOOHOONNNSOONH 3 CN

NCI Chemical Biology Consortium (CBC)Goals:• Choose high-risk targets that are of low interestto Pharma• Re-engineer investigators’ assays into highthroughputscreens• Develop screening “hits” into lead agents• Invite expert medicinal chemists to review dataand design optimized analogs• Select promising candidates based onestablished development milestones• Promote candidates with targeted activity tothe clinicThe process for accomplishing CBC goals is basedon the drug discovery strategy used by Pharma.The CBC differs from the current NCI drug discoverymodel in that the CBC will select targets, activelyscreen for agents that affect these targets, andoptimize the “drug-like” properties of hits, ratherthan focus on developing new agents submitted byoutside investigators.The success of the CBC depends as much on theenthusiasm, intellectual talent, and experienceof NCI Project Team members as it does on thequality of the targets. These attributes, combinedwith screening and assay optimization by theNIH Roadmap Screening Centers, the resourcesof the NCI, validated disease models, imagingtechnologies, and project management, willaccelerate the progress of promising new agentsthrough the drug discovery and developmentpipeline to Phase 0/I/II clinical evaluation.The CBC drug discovery process is divided into fourdistinct stages, from screening through preclinicalevaluation of the lead candidate(s). Inherent to eachstage are Stage Gates—milestones that supporttransition of a molecule to the next stage—as wellas project management processes to document andcommunicate this progress.The stages are:1.2.3.4.Exploratory Screen Development (ESD)Screening/Designed Synthesis (SDS)Lead DevelopmentCandidate SeekingThe NCI Drug Discovery Committee and the ProjectTeam will determine the Stage Gate milestonesbefore preparing the project operational plan.They will evaluate the agent according to thesemilestones before promoting it to the next stage.Entry into the CBC pipeline can occur at anydiscovery stage, from selection of a novel cellulartarget to lead agent confirmation.The CBC will mobilize a cancer drug discoverygroup on the scale of a small biotechnologyconcern, with an R&D pipeline linked to theacademic community. The CBC will re-establishthe NCI as a world leader in innovative cancertherapeutics discovery.This document outlines the process of selectingsmall molecules as potential candidates forpreclinical development within the CBC.Automated high-throughput screening will be available tothe CBC via consortium member screening centers to identify“hits” for further synthetic optimization.

1 2Exploratory ScreenDevelopmentScreening/DesignedSynthesisObjective: Proof-of-concept for a screen againsta defined mechanistic target.The NCI Project Team will initiate an intellectual propertyplan to confirm freedom-to-operate; prepare a productprofile to describe the drug product sought, mechanism ofaction, and pharmacodynamic (PD) and pharmacokinetic(PK) targets; and prepare a project operational plan tooutline project governance and support.The team will then collaborate with the screening centerto develop and validate a high-throughput assay toscreen natural product and small molecule repositoriesfor drug candidates.Objective: Identify and produce at least one highqualitylead agent from initial screening and screeningvalidationefforts.The Project Team will review the lead compoundcriteria for quality, including potency, structure–activityrelationship, activity in vitro, and safety. Team projectmanagers will prepare a detailed timeline and budgetfor lead development.Data generated from the screening and hit confirmationprocess will be accessible to all team members andSenior Management.Exploratory Screen DevelopmentGuidelines1. Initiate intellectual property plan2. Prepare product profile3. Develop screening strategy4. Identify potential biomarkers(efficacy/surrogate)5. Develop strategy for clinical readiness6. Prepare medical needs assessment7. Prepare project operational planScreening/Designed Synthesis Guidelines1. Assess mechanism of action for link to disease2. Determine desirable potency3. Demonstrate evidence of structure–activityrelationship4. Evaluate functional activity in vitro5. Determine selectivity for target6. Evaluate physicochemistry(Rule-of-Five compliant)7. Evaluate pharmacokinetics8. Assess amenability to synthesis9. Evaluate stability10. Prepare clinical plan outlineMeasure of SuccessDemonstration of project proof-of-concept and developmentof an assay suitable for screening libraries foragents with targeted activity.Measure of SuccessIdentification of one or more high-quality lead agentsand consensus that they are viable candidates forfurther development.Required for Next StepCompletion of a project operational plan summarizingthe successful completion of project milestones listedabove for presentation to Senior Management and DrugDiscovery Committees.Required for Next StepEndorsement by the Drug Discovery Committee ofa lead candidate timeline, budget, and clinical planoutline.

3Lead DevelopmentCandidate4SeekingObjective: Improve and optimize lead agent characteristicsthrough the application of medicinal chemistryto allow selection of the most promising candidatedrug. Lead compound criteria for quality must be metfor a lead agent to become a clinical candidate.Objective: Select the single most promising candidatedrug from the list of lead agents. This decisionmay involve more advanced testing of several agentsand will culminate in the preparation of a candidatealert notice (CAN) to guide the clinical developmentplan. The CAN outlines the resources needed, benefits,costs, and risks of the project, and includes a summaryof the scientific rationale for the candidate and how thissupports clinical proof-of-concept.Lead Development Guidelines1. Establish laboratory objectives for clinicalefficacy2. Resolve intellectual property issues3. Evaluate activity in validated disease models4. Evaluate physicochemistry and formulation5. Assess achievability of human PK/PD profile6. Evaluate differentiation in preclinical models7. Evaluate preliminary safety issues8. Validate biomarker(s)9. Assess feasibility of scale-up and bulk synthesisCandidate Seeking Guidelines1. Evaluate synthesis2. Evaluate biopharmaceutical properties3. Assess absorption (rodent and non-rodent)4. Determine clearance and oral bioavailability5. Assess potency against clinical efficacy6. Evaluate biodistribution7. Evaluate clinical readiness as apharmacodynamic marker8. Assess amenability to imaging9. Evaluate safety issues (most sensitive species)Measure of SuccessThe lead agents have favorable PK/PD/toxicity profiles,and there is reproducible, statistically significantevidence of targeted activity in vitro and in vivo.Measure of SuccessPreparation of a candidate alert notice.Required for Next StepCompletion of a report summarizing the projectactivities listed above, and endorsement of candidateseekingactivities by the Drug Discovery Committee.Required for Next StepEndorsement of the CAN by both Discovery and DevelopmentCommittees, approval for IND-enabling studies,and endorsement of a clinical development plan.

CBC GovernanceCBC Senior ManagementExternal (SEP) and Internal DrugDiscovery CommitteesExternal (SEP) and Internal DrugDevelopment CommitteesPortfolioAnalysisProjectStatusResourceAllocationProjectPrioritizationProject Management OfficeProjectPlanningProgressManagementDocumentManagementDecisionMakingProject Team and Lead InvestigatorExploratory ScreenDevelopmentScreening/DesignedSynthesisLeadDevelopmentCandidateSeekingClinicalTrialThe CBC Senior Management Committee will beresponsible for strategic focus, resource allocation,and project oversight and accountability.The NCI Early Drug Discovery Committee willoversee all discovery projects in the NCI pipeline,guide allocation of resources, and develop strategicplans for projects in the early discovery phase.The committee will perform risk assessments andmake Go/No-Go decisions at each Stage Gate. Akey responsibility will be to endorse preclinicaldevelopment plans.The NCI Drug Development Committee willendorse the critical transition of clinical candidatesfrom discovery phase to development phase andoversee completion of all late-stage preclinicalstudies. The committee will assess candidateeligibility for Phase 0/I/II clinical evaluation andmake appropriate Go/No-Go decisions. Thecommittee will also ensure that resources arefocused on the most important and promisingclinical opportunities.External Drug Discovery and DrugDevelopment Special Emphasis Panels (SEPs),comprising chemical biology and drug discoveryexperts from Pharma and academia, will advise theCBC on targets and molecules, approving projectmilestones, and prioritizing projects within theCBC portfolio. Project management is a criticalcomponent of all aspects of the CBC.The Project Management Office (PMO) willintegrate and coordinate the efforts of all CBCcontributors—Senior Management, Discovery andDevelopment Committees, project teams, leadinvestigators, contractors, medicinal chemists, assaydevelopers, and drug screeners—to ensure activityis focused on achieving Stage Gate milestones. ThePMO will provide writing, document management,and training support to the CBC. The PMO will alsomeasure and track CBC portfolio activities for SeniorManagement and the SEPs.

Project managers in each project team will havethe following tasks:• Work with the lead investigator and other teammembers to prepare the operational plan foreach new project based on Discovery Committeerecommendations• Develop work breakdown structures, timelines,and templates to track project status anddeliverables• Document milestones and progression• Prepare quarterly reports for the CBC Discovery,Development, and Senior ManagementCommitteesSupporting tools and infrastructure for the CBCwill consist of enterprise-wide software systemsto manage data, documents, projects, and projectportfolios. For example, a database designed toaccommodate screening data and to supportactivities related to structure-based drug discovery(SBDD) will be a shared resource for all screening,assay, and hit-optimization data generated duringdrug discovery. The data will be available toteam members and the CBC Senior ManagementCommittee to support resource management anddecision making.Example of a Drug Development Project Tracking Table2008 2009Lead Development Stage A S O N D J F M Performance IndicatorTarget Concept & Intellectual Property FTODisease ModelsPhysiochemistry and FormulationStabilityMetabolismPharmacokineticsPharmacodynamicsSafetyClinical Efficacy ObjectivesScale UpClinical ProductTeam project managers will provide tools to track and communicate project status, coordinate team activities, andhighlight process issues. The tools allow the progress of each project to be followed through the drug discovery anddevelopment pipeline, which helps with the planning and coordination of the different tasks at each stage.For more information, please visit theNCI DCTD Web site: http://dctd.cancer.gov

CHEMICAL BIOLOGY CONSORTIUMAugust 2008