• Solicitation Status Awarded
• Date Awarded
• Research Category Research & Development Services & Subcontracts
• Solicitation Number S22-015
• NCI OA Contract Number 75N91019D00024 – NCI-FFRDC

Description

The NExT program seeks to identify CBC Centers that can provide deep scientific expertise, highly skilled technical capabilities and resources to fulfill the essential activities necessary to advance early stage drug discovery projects through the Candidate Selection phase. Certain areas of expertise are commonly required for almost all early discovery projects. However, some projects either require, or may benefit greatly from the application of more specialized technologies. To support a diverse portfolio of NExT discovery projects in an optimal fashion, the CBC will be composed of Centers staffed with personnel experienced in a variety of fundamental discovery competencies as well as Centers with a more specialized set of skills or advanced technologies to provide alternative or cutting edge approaches for projects that would benefit from such methodology.

In addition to having strong scientific and technological capabilities, CBC Centers also must have personnel who can collaborate effectively with other scientists on a multidisciplinary project team. The PI from each Center is expected to participate actively as a member of the CBC Steering Committee and to contribute insightful perspectives that benefit the CBC as a whole.
Lastly, CBC Centers will need to provide appropriate management oversight to effectively support their scientific contributions to NExT projects and the CBC. Such responsibilities include handling personnel and staffing requirements to effectively support project teams, accurately processing contractual and financial documents in accordance with guidelines provided by the Leidos Biomed Contracting Office, and managing spending on project team activities so as to stay within budget.
A.2. Scientific and Technical Capabilities
The CBC will possess a broad range of fundamental and specialized capabilities that can be deployed effectively to tackle each drug discovery project. The technologies and skills listed in the table below, and elaborated upon in the following paragraphs, indicate the categories of skills and expertise essential for supporting NExT projects through the Candidate Selection phase. Within these categories, there are many commonly used techniques and approaches to accomplish the goals, and the CBC will include Centers that are well versed in these methodologies to provide adequate support for the portfolio of projects. However, within each of these categories there also exist specialized techniques or methods that can provide a unique advantage for targets not well-suited or amenable to more traditional approaches. Because of NExT’s mission, its discovery projects often tackle novel targets and nontraditional mechanisms of action that may benefit from these specialized approaches. Thus, it is essential that this Solicitation identify not only Centers with deep expertise in traditional drug discovery methods but also Centers with specialized methods and innovative technologies.
Categories of Technologies and Skills Essential for Drug Discovery to be Provided by the CBC
1. Protein production and purification for HTS, SAR assays and structural biology studies
2. Development of biochemical and cellular assays, including optimization and miniaturization for HTS
3. HTS capabilities—technology platforms to assay enzymatic activity, ligand binding, fragment screening and cellular readouts, including high content methods, coupled with robust compound management and data handling. Unique screening technologies for “difficult” targets are sought.
4. Cancer cell biology expertise—deep knowledge of the molecular mechanisms and parameters controlling cancer cell growth, tumor initiation, progression and metastasis. Ability to translate this knowledge into development of relevant pharmacodynamic markers as well as assays and experimental systems that can be used to evaluate lead compounds, assess target engagement and demonstrate on-target efficacy. For early stage projects, this knowledge will be applied to devise target validation criteria. Expertise in technologies for cell line phenotyping and engineering (e.g., with CRISPR) and to conduct studies to identify mechanisms of action, drug sensitivity and resistance. Familiarity with quantitative assays to evaluate gene expression, epigenetic modifications and chromosomal interactions (e.g., DNA and histone methylation status, ChIP-seq) will be required.
5. Structural biology (X-ray crystallography, protein NMR, single particle cryo-EM) and biophysical characterization methods (e.g., surface plasmon resonance (SPR), isothermal titration calorimetry (ITC))
6. Chemistry— chemists with a thorough knowledge of modern medicinal chemistry principles and who are highly skilled in synthetic organic strategies and methodologies. Expertise in structure-based design of new analogs as well as fragment linking, merging and expansion approaches.
7. Computational Assisted Drug Design (CADD) – predictive modeling of compound binding modes, docking scores, virtual screening methods and molecular dynamics simulations incorporating the latest artificial intelligence and machine learning methods.
8. Biochemical compound selectivity profiling and in vitro ADME—panels of assays of diverse enzymes, ion channels, receptors, cytochrome P450s, etc and assays of compound solubility, microsome stability, logD determination, cell permeability, etc
9. Cellular compound profiling – a diverse set of >100 cancer cell lines for growth inhibition studies and correlation of sensitivity with genetic profile, cyp P450 induction, hERG or related cardiac safety assessment
10. In vivo studies—PK in various species (e.g., mouse, rat, dog, non-human primate), PD assays of tumor tissue, determination of MTD and efficacy (in xenograft or genetically engineered mouse models), metabolite ID, exploratory toxicology studies
11. Omics technologies – genomic or exome sequencing, mRNA expression profiling, mass spec-based proteomic analysis, ChIP seq, single cell analyses and other leading edge, unbiased genome-wide approaches to help characterize compound mechanism of action and selectivity in cells and animal models
12. Scale-up synthesis and formulation to support in vivo studies

Proposal Instructions

Please request copy of RFP S22-015 via email cbcproposals@mail.nih.gov