RIKEN Program for Drug Discovery and Medical Technology Platforms

Guideline

Guideline
Approach to Selecting Drug Discovery Themes and Projects

 For the Drug Discovery and Medical Technology Platforms, we have established the six guidelines (standards) shown below concerning the selection of topics targeted for support by the drug discovery themes and projects within RIKEN and elsewhere. Formulating these standards is positioned as part of the drug discovery exit strategy. At the start of the research, they have been established to facilitate the focus and selection of topics of significance for academic research with high potential for successful drug discovery research.


Table1. Guidelines

1.Is it an area of disease where RIKEN should be engaged?
  • Low levels of therapeutic satisfaction, areas where drug contribution is low.
  • In particular, orphan drugs and neglected drugs.
2.Novelty and reliability of the mechanism (CIM)
  • Creative and highly reliable.
3.Potential for investigating promising candidates for pharmaceuticals
  • Low molecular, if possible with well-known protein structure, and deep binding sites.
4.Prior drugs
  • Non-prior drugs are preferable. Potential for differentiation in certain cases.
5.Is there already some progress in the stages of the research?
  • Prioritize research that has progressed further through the stages.
6.Does the proponent have the enthusiasm and time to actively push for drug discovery?
  • As theme leader or project leader, the proponent will tackle the drug discovery research with enthusiasm and not as a sideline.


Table2. Outlines the details of the assessment

Known Information (Protein structure, chemical compound, the literature) Protein ID Accession No.
Protein structure Structure / RIKEN
Structure / PDB
Chemical journals Inhibitor
Biological journals Mechanism
Development stages for advanced items biological testing
preclinical
P1
P2
P3
Launched
Theme Assessment Guidelines (Details) Theme outline Treatment satisfaction level
Marketability
Prior drugs
Creativity
Methods of differentiation from prior drugs
Proposal intent Supporting research results
Drug efficacy in the animal model
Are specific differences clear?
Assessment system
Preference or absence of appropriate animal models
Biomarkers
Association with disease
Safety Safety of the mechanism
Technology Druggability of binding sites


Assessment and Methods of Selection Based on the Selection Guidelines

1. Is it an area of disease where RIKEN should be engaged?
 Categorizing areas of disease for drug discovery themes and drug discovery classification, we prioritize drugs for treating epidemics in developing countries (neglected diseases), drugs for treating diseases where the number of patients is few (orphan drugs) and areas of disease with low levels of treatment satisfaction and no effective drugs. (The red areas in the diagram below indicate strong areas.Click here for more details.) We also give preference to the selection of innovative drug discovery and medical technology based on new concepts capable of capitalizing on the results of basic research by RIKEN and academic research institutions.

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2. Novelty and reliability of the mechanism (CIM)
 The mechanism for drug discovery themes requires the compatibility of two contradictory items: novelty (drug discovery data based on unprecedented new molecular mechanisms) and reliability (referred to as confidence in mechanism, abbreviated CIM. In the drug discovery field, this indicates confidence that the molecular mechanism of the target is linked to the actual treatment due to drug efficacy in knockout animals, siRNA or disease animal models.). We collect and evaluate information based on published and unpublished data by the proposing laboratory as well as a diligent examination of the literature.

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3. Potential for investigating promising candidates for drugs
 Even when the target presents some novelty and the therapy is sufficiently reliable, it is not possible to reach the patient if tying in with actual “pharmaceuticals” proves difficult. Even in cases that are difficult under normal conditions, there are cases where the basic technologies of RIKEN can turn the impossible into the possible. If it is a question of low molecular targets, we investigate in great detail whether the structure is already understood through x-rays or NMR, whether structural analysis is possible at RIKEN, and whether or not the structure of the target has binding sites where low molecules can be strongly bound (see diagram below). With respect to antibody drugs, nucleic acid drugs and cell therapies, we determine the order of preference by assessing whether or not the targets and areas of disease are ones where the sophisticated RIKEN technologies can be put to practical use.

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4. Presence or absence of prior drugs and differentiation
 It is preferable that the targets for involvement are completely new targets with no prior drugs, but in case of prior drugs, we investigate what stage they are at and their weaknesses. In the Drug Discovery and Medical Technology Platforms, we have put together a system capable of searching several millions of entries in inhibitor databases such as the Thomson Reuters database and ChEMBL for prior drugs, and if there is a prior drug, to analyze the potential for differentiation.

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5. Is there already some progress in the stages of the research?
 Another important topic for investigation is to what degree there has been progress in the stages of a previously identified chemical compound from the perspective of drug discovery themes. Our program divides the stages into three classes: the S (seed) stage, the L (lead) stage and the P (clinical) stage with further subdivisions for each stage of S0 to S3, L1 to L3 and P0 to P3. Please see here for definitions. The theme extends from the S1 to the L2 stages, which is the investigative stage before we narrow down the candidate compounds to one or a small number. This is when the theme leader and portfolio manager (the portfolio manager is responsible for several themes) work together to drive drug discovery. The project refers to the L3 stage and beyond, which is the development stage for the candidate compound when we assign a project leader to push hard for development. In order to judge these stages, the program collaborates with internal and external partners to ready a structure for pharmacological testing of drug efficacy and all types of ADMET testing in addition to activity toward the target.


Please see below for definitions of each stage.

guideline_fig7

  • S0:Identify the target
  • S0S1:Construct screening systems and undertake screening
  • S0S2:Find a hit compound and develop seeds
  • S0S3:Find a promising drug discovery seed and develop leads
  • S0L1:Find responsive lead compounds as a result of animal testing, optimization
  • S0L2:Identify several promising compounds, optimization in order to progress to GLP testing
  • S0L3:Select P0 candidate compounds as a result of non GLP testing
  • S0P0:Select candidate compounds as a result of GLP testing
  • S0P1/P2/P3:Correspond to Ph I/II/ III of clinical testing


With respect to the important stages among the above, we make detailed decisions on the definitions for moving up to the next stage.

 

6. Does the proponent have the enthusiasm and time to actively push for drug discovery?
 In drug discovery, it is essential that researchers from many specialist fields collaborate closely while pushing tenaciously forward. It is also essential to administer the themes by assessing successive outcome of the test data in a timely manner. Therefore, the theme proponent is interviewed by the coordinator and the portfolio manager while polishing the proposals together. When making decisions about which themes to push, we also take into account whether or not all proponents have the enthusiasm and sufficient research time to spend on drug discovery.



Order of Preference for Themes

→B and above are the focus themes
→We refer to assessment ratings and aggregate results to determine final order of preference 


Table3. Order of Preference

Order of preferenceDefinition
A Themes for extensive engagement in the drg discovery program Commit all necessary infrastracture (platforms)
B There are several points for confirmation, there is partial involvement in the drug discovery program for purposes of confirmation. If the points for onfirmation are resolved, the theme is elevated to category A, or stays in category B but with a gradual increase of invested effort. Commit partial infrastracture (platforms)
C There are several problem points, the drug discovery program provides advice to facilitate solutions. Partial engagement if there is scope. Advice or partial commitment of infrastracture (platforms)
Watch The research is valuable if the circumstances change, advice on developing drug discovery themes. Advice



Standards for progressing to the next stage
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Please contact us for consultation

 There are many topics that must be clarified before implementing drug discovery. (Please refer to the diagram below.) We have taken these topics into account when establishing the guidelines. Our program is staffed with specialists in drug discovery together with researchers who are knowledgeable about sophisticated drug discovery technologies. We have put in place a structure capable of promoting drug discovery themes and drug discovery projects for everyone. Do be sure to consult with us.

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