Florida Translational Research Program (FTRP)

Transcription

1 Florida Translational Research Program (FTRP) Solicitation of Concept / Assay Development (CAD) Projects for use in Pre-Therapeutic Discovery via High-Throughput Screening (HTS) Purpose of the Program The purpose of the Florida Translational Research Program (FTRP) is to produce a pipeline of potential new medicines based upon laboratory research discoveries. The program provides Florida-based scientists with access to experienced professionals and state-of-the-art technological resources for drug discovery in an effort to facilitate the advancement of potential new drug treatments for today s most prevalent medical needs. The program is funded by the State of Florida through the Florida Department of Health and is administered and executed by Sanford-Burnham Medical Research Institute (SBMRI) at Lake Nona. Executive Summary The purpose of this announcement is to invite Florida-based investigators to join efforts with the Conrad Prebys Center for Chemical Genomics at SBMRI at Lake Nona to develop concepts and assays for high throughput screening (HTS) with the intent of using them to screen for small molecule compounds that show desired properties as pre-therapeutic leads. At the end of the project period, a successful project will have developed one or more HTS-ready assays to identify molecules that affect the biology of interest. Ultimately, this solicitation seeks to establish a stream of scientifically sound and technologically feasible assays for screening by the Conrad Prebys Center for Chemical Genomics at SBMRI. Assays may involve targets indirectly related to disease but which might provide insight into the biology of relevant diseases. Other targets might be associated with rare and neglected diseases. Eligible organizations: Eligibility for this Program is limited to universities, colleges, and non-profit research institutes in the state of Florida. Any individual who is authorized by his or her organization to apply for state and federal grants, and possesses the skills, knowledge, and resources necessary to carry out the proposed research as the project director or principal investigator (PD/PI), is invited to work with his/her organization to develop an application for support. The total number of projects to be selected depends on the scientific merit of applications and the availability of resources within the FTRP. There are no funds associated with selection for the program. The FTRP will support the costs of assay feasibility and development experiments at SBMRI at Lake Nona. There is no limit to the number of applications an applicant may submit under this announcement. Likewise, there is no limit to the number of applications that may be selected from an organization or a PD/PI. Please note the special receipt dates listed under Key Dates. Objective of this Call for Proposals The over-arching objective of this announcement is to invite proposals for the development of innovative biochemical and cell-based assays for biological targets or processes for which there are limited selective and potent small molecule modulators available. Sanford-Burnham Medical Research Institute at Lake Nona Page 1 of 8

2 Guidance for CAD Assay Application This solicitation is divided into two objectives: 1) concept/assay feasibility and development, and 2) configuration of assays for HTS. Proposals are expected to span both aims, although more advanced proposals that are limited in scope to objective 2 will also be considered. Objective 1) Concept / assay feasibility and development. Applications are invited from investigators who, as a result of their independent research efforts, have identified a potential new drug target and who desire to work with SBMRI to develop a cascade of in vitro assays suitable for HTS to identify small molecule modulators of the target of interest. Investigators will collaborate directly with the drug discovery team at SBMRI to review targets, assay concepts, know-how, reagents, and protocols from the investigator s existing portfolio of assays and reagents; to then develop a practical assay concept and work plan to generate the required reagents; and to deliver a workable prototype HTS assay (of at least 384-well format). The professionals at SBMRI may further miniaturize and optimize to a 1536-well format for the purpose of producing pilot HTS data in this final format. The data generated may include confirmation of automated assay robustness (Z >0.5, S/B >4, CV <10%) and pilot screening of a small (~2K compounds) library to establish the approximate hit rate for the primary assay. The team will also develop a plan for a cascade of follow-up assays (orthogonal, counter-screen, selectivity), demonstrate that these assays can support quantitative dose-response studies, and, where possible, generate actual data on pilot hits through this cascade. This solicitation is intended to cover a wide array of potential drug targets. Targets may be any of the three types below: Defined molecular targets (e.g., GPCRs, nuclear receptors, kinases, etc.) Biochemical or cellular pathway targets (e.g., activation of a select phosphorylation cascade) Phenotypic targets (e.g., intracellular translocation of target, neurite extension/retraction, lipid accumulation, etc.) Preliminary data regarding the validation of the target are highly desirable. Such data may be derived from clinical or preclinical observations, and may be obtained from in vitro experiments or in vivo studies. For example, data linking a given target to the pathogenesis of disease using transgenic (knock-out, knock-in, etc.) mice, or obtained from the use of normal and diseased human tissues, are useful in evaluating the therapeutic utility of a compound acting at the proposed target. For this objective, preliminary data regarding the specific assay to be developed are not required or expected. Objective 2) Configuration of assays for HTS. Applications are also invited from investigators who, as a result of their independent research efforts, have identified a potential new drug target and have developed an in vitro assay that requires adaptation and configuration for HTS to identify small molecule modulators of the target of interest. Investigators will collaborate directly with the drug discovery team at Sanford-Burnham to assess the assay, reagents, and protocols from the investigator s existing portfolio; to then develop a practical work plan to generate the required reagents; and to deliver a workable prototype HTS assay (of at least 384-well format). The professionals at Sanford-Burnham may further miniaturize and optimize to a 1536-well format for the purpose of producing generate pilot HTS data in this final format. The data generated may include confirmation of automated assay robustness (Z >0.5, S/B >4, CV <10%) and pilot screening of a small (~2K compounds) library to establish the approximate hit rate for the primary assay. The team will also develop a plan for a cascade of follow-up assays (orthogonal, counter-screen, selectivity), demonstrate that these assays can support quantitative dose-response studies, and, where possible generate actual data on pilot hits through this cascade. Sanford-Burnham Medical Research Institute at Lake Nona Page 2 of 8

3 Areas of interest. Relevant areas of interest include but are not limited to the following: assays for molecular chaperones or molecules that improve the post-translational targeting, folding, or assembly or proteins, especially involving mutant proteins responsible for inborn errors of metabolism, metabolic disorders, cancers, or rare diseases; assays for compounds that modify the function of signaling complexes, regulatory networks, and sorting machinery; biochemical or cell-based assays of activity, behavior, or interaction of proteins (e.g., protein:protein interaction or protein:chromatin interaction) and other molecules of interest; assays of cellular or molecular phenotypes; modulation of expression of genes of interest, including effects on transcription factors, transcription, translation, or RNA splicing; and whole-cell assays that employ engineered cells rendered hypersensitive to a targeted pathway. The following are types of applications that are NOT appropriate for this solicitation: applications for the execution of a screen using an existing HTS-ready assay not requiring assay development for screening, or in which prototype molecules have been identified. Individuals proposing these kinds of activities should apply to the companion solicitations (high-throughput screening [HTS] and hit-to-lead [HTL]) available at the FTRP website ( research focused on understanding normal biology or disease processes; and applications focused on identifying new targets. Assays. Many in vitro biological models are currently used to study biological targets and pathways, to decipher the effects of genetic perturbations on their function, and to establish a possible disease association. These models can be adapted to high-throughput formats for the purpose of screening large collections of compounds with potential biological activity. There are a number of characteristics that make an assay suitable for its adaptation to a high-throughput approach. The assay must be robust and reproducible with a readout that is amenable to automated analysis. In addition, the work proposed must lead to miniaturization of the assay to a 96-well plate (or higher density) format. Further, the assay protocol should be simple enough for automated handling. A broad range of models share many of these features, including biochemical assays, cellular models, and certain model organisms. Emphasis will be placed on novelty of assay approach and novel targets and mechanisms. Appropriate assays might include but are not limited to: biochemical or cell-based assays of activity measuring target interactions involving small molecules, peptides or other biological molecules; cell-based assays measuring cell signaling or the activity of biosynthetic pathways; assays of cellular or molecular phenotypes; modulation of gene expression, including effects on transcription, translation, or RNA splicing; and assays involving mutant proteins associated with disease. Material and Data Sharing. Submitting investigators will be required to provide necessary, unique reagents that are not commercially available such as cells expressing recombinant enzymes/proteins, primary and secondary antibodies, tagged peptide substrates, and available positive controls (e.g., a known inhibitor of the target). Key Dates for this Call for Proposals Call open: March 30, 2015 Sanford-Burnham team available for questions and project mentoring: April-May, 2015 Proposal deadline: Thursday, May 28, 2015, 5:00 p.m. Eastern Awards announced: on or about July 24, 2015 Sanford-Burnham Medical Research Institute at Lake Nona Page 3 of 8

4 Award Information There is no transfer of funds associated with selection of projects for inclusion in the FTRP. Rather, successful applicants will obtain access to resources including assay automation, HTS, and synthetic chemistry capabilities that can be applied to the discovery and development of innovative chemical tools for use in biological research and as platforms for potential therapeutics development. These services will be provided by the Florida State Department of Health through SBMRI at Lake Nona. Eligibility Institutional Eligibility: Eligibility for this program is limited to universities, colleges, and non-profit research institutes in the state of Florida. Investigator Eligibility: Any individual who is authorized by his or her organization to apply for state and federal grants, and possesses the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI, is invited to work with his/her organization to develop an application for support. Application Requirements All documentation must be formatted with at least ½-inch margins on all sides, using Arial 11 pt font. The PI s name (last name, first name) should appear on the right-hand side of the header on all pages, and pages of the submission beginning with the technical proposal should be numbered sequentially starting at page 1. All applications must contain the following elements: Application Elements Project Narrative Scientific Abstract Technical Proposal Objective 1: Concept / assay feasibility and development Suggested Length 2-3 sentences Limit to 30 lines of text Approximately 3 pages plus references Drug target / pathway description Clinical / experimental evidence linking target and disease Desired mechanism of action of compound Available reagents Objective 2: Configuration of assays for HTS Assay configuration data section (signal intensity, dose-response, reproducibility) Description of proposed secondary and/or counter-screen assays Reagent availability / cost estimate NIH Biosketch Bilateral Confidentiality Agreement (BCA) * Material Transfer Agreement (MTA) References / Publications Limit to 4 or 5 pages per PI PI + co-i(s) (if applicable) No page limit No page limit No page limit Resubmission 2 pages * Please note that only one master BCA per institution is required and will be executed. If one has been executed for your institution, your institutional official should upload a copy of the signed agreement already in place. Additional details, as required, are provided below for each element. Sanford-Burnham Medical Research Institute at Lake Nona Page 4 of 8

5 Project Narrative (no more than 2-3 sentences long). Detail the relevance of the proposed research project to public health. The information should be succinct and in plain language understandable by a general, lay audience. The project narrative is made public for all awarded projects. Scientific Abstract (limit to 30 lines of text). Provide a succinct and accurate description of the proposed work when separated from the application. Include the application s broad, long-term objectives and specific aims, making reference to the public health relevance of the project. Describe concisely the research design and methods for achieving the stated goals. This section should be informative to other persons working in the same or related fields and, insofar as possible, understandable to a scientifically or technically literate reader. Avoid describing past accomplishments and use of the first person. Do not include proprietary, confidential information or trade secrets. If the application is accepted, the project summary / abstract will become public information. Technical Proposal / Project Description (limit to 3 pages not including references). Project Descriptions for Objective 1) Concept / assay feasibility and development should address the following questions: What is the proposed target (e.g., GPCR, kinase, etc.) or mechanism (e.g., PI3K pathway, MAPK pathway, etc.)? In what disease is this target or mechanism implicated and what is the evidence for disease association? What data have you produced that provides the biological rationale underlying the hypothesis that modulation of this target or mechanism will achieve the predicted effects? What would be the site of action of a modulator (e.g., intra-/extracellular, target tissue/organ, etc.)? Comment on what reagents you currently have available or could be readily produced (e.g., proteins, cells, antibodies, etc.). What structural information for the target or the ligand is available? Preliminary data regarding the validation of the target should be included, if available. Project Descriptions for Objective 2) Configuration of assays for HTS should address the following: A description of reagents and readouts currently available to the PI and that can be translated to an automated HTS environment, such as absorbance, fluorescence, luminescence, fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), biophysical readouts, and cell-based imaging screens, must be included. Assays should be easy to eventually automate and steps such as centrifugation, filtration, and extraction avoided. Assays requiring only addition of reagents, i.e., mix-and-measure assays, are preferable. Generally, the assay protocol should aim to demonstrate a signal of sufficient intensity that it can be easily measured (using for example, a microtiter plate of low volume); reproducible, dose-dependent responses to a small collection of pharmacologically active standards or reaction substrates or inhibitors; and preliminary data indicating baseline values for validation criterion, any kinetic data, and a brief description of the protocols for the current format of assays available. Demonstration that secondary and counter-screen assays are available or can be developed and characterized. Information describing reagent availability, equipment used in configuring the assays, and estimated cost per assay should be provided. Preliminary data regarding the validation of the target are desirable. Such data may be derived from clinical or preclinical observations and may be obtained from in vitro experiments or in vivo studies. For Sanford-Burnham Medical Research Institute at Lake Nona Page 5 of 8

6 example, data linking a given target to the pathogenesis of disease using transgenic (knock-out, knock-in, etc.) mice, or obtained from the use of normal and diseased human tissues, would be useful in evaluating the therapeutic utility of a compound acting at the proposed target. NIH Biosketch (limit of 4 or 5 pages per person). Provide for the PI and co-pi (as necessary). The FTRP will accept biosketches in current NIH format or the new NIH format (as described in NOT-OD ) for this call. Bilateral Confidentiality Agreement (BCA). Must be signed by an authorized institutional official from the Technology Transfer or Sponsored Research office and uploaded to the FTRP website ( prior to submitting all applications. Please note that only one master BCA per institution is required and will be executed. If one has been executed for your institution, your institutional official should upload a copy of the signed agreement already in place. If you do not have an executed agreement in place for your institution, a blank BCA template may be downloaded from the FTRP website. Please check with your institutional official for more information. Material Transfer Agreement (MTA). Must be signed by the PI or other authorized institutional official from the Technology Transfer or Sponsored Research office. This document is available on the FTRP website ( References / Publications (no page limit). Include a list of any publications that support or describe the proposed assays. Resubmission (limit of 2 pages). The resubmission document must contain a numbered, point-by-point statement of how you have responded to the criticisms raised. This statement should not exceed two pages. Highlight the changes to your proposal within the main document either by using the track changes feature in Microsoft Word or by using bold or colored text. To assist you in this task, experts from the Sanford-Burnham team are available for discussion of technical aspects of the proposed approach and to provide guidance on the revision. Contact ftrp@sanfordburnham.org to arrange a conference. Please note that submission of a revised proposal does not guarantee its acceptance. How to Submit Applications Authorized institutional officials must submit applications via the FTRP website ( Prior to submission applicant organizations must register with the FTRP submission website. All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process early to avoid possible delays in submission. All applications must be uploaded to the FTRP portal and submitted by an authorized institutional official following the instructions provided herein. Please note that applications sent by any other means, e.g., hand-carried, postal service mail, commercial carrier, fax, or , will not be considered. For Institutional Officials: To begin, the institutional official must register their organization in the FTRP website. After the institutional official has registered their organization, they can begin creating application packages. Note that registration for previous cycles is sufficient; it is not necessary to register more than one time. Please see the FTRP portal for more information on how to register an organization and assemble application packages. Once registered, the institutional official will have the option to either create applications on behalf of their PIs or can create sub-user accounts for their PIs. Authorized PIs are able to create application cover sheets and upload all required proposal documents; however, only institutional officials are able to officially submit applications on behalf of the organization. If a PI has a sub-user account for access to the portal, the PI is responsible for uploading all required documentation. Once a PI has completed their application package, the institutional official will receive an notifying them that there is a completed application package ready for their review. Institutional officials must review all applications and are responsible for submitting them to FTRP on behalf of the organization by the deadline detailed in this call. Sanford-Burnham Medical Research Institute at Lake Nona Page 6 of 8

7 For PIs: PIs should not attempt to register on the portal or submit proposals on their own. Institutional officials must register the organization in the FTRP portal. PIs should contact the institutional official at their organization and notify them of their interest in applying to the program. All PIs must work with their institutional officials to register with the FTRP submission website to ensure an institutional account is active and the individual PI is affiliated with the account of the applicant organization. Sub-user accounts will allow the PIs access to the portal and will enable them to create and assemble their application packages. Once completed, the PI must use the portal to send their application packages to their institutional officials for review. PIs cannot submit their applications directly to the FTRP. Only an institutional official can submit the application to the FTRP on behalf of the organization after completing a final review of the package. All application packages will be considered works in progress and will not be accepted for evaluation until the institutional official submits the final application package. An acknowledgement of application receipt will be provided to the submitter via . Upon submission, applications will be evaluated for completeness by the FTRP program staff. Applications that are incomplete will not be reviewed. Applicants are strongly encouraged to submit their proposals well in advance of the deadline to ensure they have time to make any corrections that might be necessary for a successful submission. Selection Process Complete applications will be evaluated for technical feasibility and scientific merit by an appropriate review group convened by the FTRP, administered by Sanford-Burnham. Technical Feasibility Review Committee. Evaluate assay proposals for HTS feasibility as configured using the current infrastructure and capabilities of the Conrad Prebys Center for Chemical Genomics at SBMRI at Lake Nona. The panel members will be scientists with sufficient expertise and knowledge to evaluate the technical feasibility of the proposed assay. Assays will receive a simple go/no-go assessment from the committee. Proposals that are determined not to be feasible (no-go) will not be communicated to the Scientific Merit Review Committee. Scientific Merit Review Committee. An external panel of experts, representing universities, government agencies, and private industry outside the state of Florida, evaluates assay proposals for scientific merit, novelty of the target, potential for addressing an unmet medical need, and potential for commercialization. FTRP Steering Committee. Review summary statements from the Scientific Merit Review Committee and develop a balanced portfolio that is consistent with program priorities, existing capacity of the SBMRI Conrad Prebys Center for Chemical Genomics, cost, workload, detection system, etc. Notifications Applicants will be notified of proposal disposition via . These s will contain a written critique of the proposed project. Unsuccessful applicants will be provided with a brief assessment of possible steps to take to improve potential future success. Resubmissions For resubmissions, the committee will evaluate the application as presented in the resubmission documentation, taking into consideration the responses to comments from the previous scientific review group and changes made to the project. As with NIH, applications to the FTRP are limited to two submissions (an original submission and a single revised resubmission). Information on Terms, Conditions, and Required Reports All applicants are required to complete a material transfer agreement (MTA) and confidentiality agreement (BCA) with the SBMRI at Lake Nona. (See page 6 for more details.) Sanford-Burnham Medical Research Institute at Lake Nona Page 7 of 8

8 Submitting investigators will be required to provide necessary reagents such as cells expressing recombinant enzymes/proteins, primary and secondary antibodies, tagged peptide substrates, and available positive controls (e.g., a known inhibitor of the target). Successful applicants must provide 1) a project report to the FTRP within 90 days of project completion and 2) annual updates on long-term FTRP participation success for up to five years post project completion to include grant awards, resulting intellectual property (i.e., patent filings), and related publications. Publications related to the results obtained from the project must acknowledge support by the state of Florida, the Florida State Department of Health, and SBMRI at Lake Nona. Intellectual property inventorship will be determined according to U.S. Patent Office rules and as defined in the material transfer agreement or subsequent inter-institutional agreement. Contacts Scientific and Technical Questions: Layton Harris Smith, Ph.D. Director, Drug Discovery Florida Assistant Professor SBMRI at Lake Nona 6400 Sanger Road Orlando, FL lhsmith@sanfordburnham.org Scientific / Technical and Administrative / Programmatic Questions: Philip Arlen, Ph.D. Associate Director, Outreach, Alliances & Partnerships SBMRI at Lake Nona 6400 Sanger Road Orlando, FL parlen@sanfordburnham.org Administrative and Programmatic Questions: Sonja Gyimah Senior Project Coordinator, Florida Translational Research Program SBMRI at Lake Nona 6400 Sanger Road Orlando, FL sgyimah@sanfordburnham.org Sanford-Burnham Medical Research Institute at Lake Nona Page 8 of 8