Testing of small molecule compounds for optimization of biochemical, physiochemical and pharmacokinetic properties

INTRODUCTION
This is a Small Business Sources Sought (SBSS) notice. This is NOT a solicitation for proposals, proposal abstracts, or quotations. The purpose of this notice is to obtain information regarding: (1) the availability and capability of qualified small business sources; (2) whether they are small businesses; HUBZone small businesses; service-disabled, veteran-owned small businesses; 8(a) small businesses; veteran-owned small businesses; woman-owned small businesses; or small disadvantaged businesses; and (3) their size classification relative to the North American Industry Classification System (NAICS) code for the proposed acquisition. Your responses to the information requested will assist the Government in determining the appropriate acquisition method, including whether a set-aside is possible. An organization that is not considered a small business under the applicable NAICS code should not submit a response to this notice.

This notice is issued to help determine the availability and type of qualified Small Business companies technically capable of meeting this potential government requirement and to determine the method of acquisition. It is not to be construed as a commitment by the Government to issue a solicitation or ultimately award a contract. Responses will not be considered as proposals or quotes. No award will be made as a result of this notice. The Government will NOT be responsible for any costs incurred by the respondents to this notice. The notice is strictly for research and information purposes only.

The information requested will assist the Government in determining the appropriate acquisition method including small business socio-economic set-aside possibilities and to determine the availability of qualified Small Business companies technically capable of meeting the Government's potential requirement. All Small Business companies with the capability and availability to perform the requirement under the applicable NAICS code are invited to submit a response to this notice.

NORTH AMERICAN CLASSIFICATION SYSTEM (NAICS) CODE
The NAICS code applicable to this requirement is 541380-Testing Laboratories with associated small business size standard of 15 Million USD.
BACKGROUND
The National Institutes of Health (NIH) is the nation's leading medical research agency and the primary Federal agency whose mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability, conducting, supporting and making medical discoveries that improve people's health and save lives. The National Center for Advancing Translational Sciences (NCATS) is a translational science center that prides itself on its tremendously productive pipeline and is innovative in a number of ways. NCATS brings together a diverse range of scientists, including medicinal chemists, biologists, toxicologists, and engineers, in order to ultimately translate basic science into real products and services that help improve people's lives. Included in this process is the development of unique chemical material as a probe to investigate the mechanisms of diseases and to potentially assist in the development of new methods of treating such diseases.

Prior work at NCATS has produced a series of small molecule IRAK4 / FLT3 kinase dual inhibitors, including NCGC00371481 and its structural analogs. Compounds such as '1481 have shown promising results in cellular and mouse models of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Further optimization of the biochemical, physiochemical and pharmacokinetic properties of these compounds is required, and may eventually produce a clinical candidate that could be used to treat cancers such as MDS and / or AML.

In order for a candidate compound to advance into clinical trials, it must display a wide range of acceptable properties. For this program, the compounds must display potent inhibition of the desired targets (IRAK4 and FLT3). They must also display a non-negligible free fraction (the percent of total drug that is not bound to plasma protein) in order to efficaciously engage their targets in vivo. When drugs are dosed in preclinical species (mouse, rat, dog or monkey) or in humans, they enter into systemic blood circulation. There, blood plasma proteins such as albumin are often effective at binding to drugs, and in many cases, a significant percentage of the drug that is in circulation is plama protein-bound. Importantly, the portion of drug that is bound to plasma protein is not available to act at its desired target. Only the unbound portion is free to act at the target to produce the desired effect. Because drugs have widely varying propensities for binding to plasma protein, the percentage that binds to such protein (and the corresponding free fraction) must be determined experimentally. In order for doses to be properly calculated, it is essential to know the unbound fraction of a drug, as a drug given at a certain dose (for example, 100 mg) would yield only a low level of unbound drug (the active species) if plasma protein binding is high (for example, 99%), but a much higher level of unbound drug if plasma protein binding is moderate (for example, 20%).

For a given compound, binding to plasma protein may vary across species. That is, binding to mouse, rat, dog, monkey or human plasma proteins may vary. For that reason, preclinical drug discovery programs that test in a variety of preclinical species, and that ultimately want to advance compounds into human clinical trials, will ultimately need to be able to test for plasma protein binding against mouse, rat, dog, monkey and human plasma proteins.

Testing of a set of 20 small molecule compounds for binding to mouse and human plasma protein will allow a determination of the compounds' free (unbound) fraction in the presence of such proteins, and will provide essential information that will aid in dosing calculations for preclinical and clinical studies.

Purpose and Objectives
This Small Business Sources Sought notice seeks to determine eligible sources capable of achieving the essential features of this potential requirement. The purpose of this potential requirement is to obtain results for the following types of testing on four studies:

1. Testing of twenty (20) small molecule compounds for binding to mouse and human plasma protein.

2. Testing of thirty (30) small molecule compounds for activation of the PXR and AhR nuclear receptors.

3. Testing of ten (10) small molecule compounds for inhibition of the CYP enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

4. Testing of sixty (60) small molecule compounds for inhibition of the CYP enzymes CYP2C9, CYP2D6 and CYP3A4.

Project Requirements
This Small Business Sources Sought notice seeks responses from qualified sources that are capable of providing the following salient service requirements of this potential government requirement deemed as the essential features needing to be achieved. Specifically, Offerors to this Small Business Sources Sought notice shall possess the capability to provide the following types of testing as essential requirements:

1. Plasma Protein Binding Study - (NCATS_PPB_03082019) Contractor will:

a.) Test each of 20 small molecule compounds for binding to mouse and human plasma protein.

b.) Provide a comprehensive report with the results of the experiments of each of the 20 compounds tested for binding to mouse and human plasma protein.

2. PXR and AhR Study - (NCATS_PXR_03082019) Contractor will:

a.) Test each of 30 small molecule compounds for activation of the PXR and AhR nuclear receptors.

b.) Provide a comprehensive report with the results of testing the 30 compounds for activation of PXR and AhR.

3. CYP Inhibition Study - (NCATS_CYP10_03082019) Contractor will:

a.) Test each of 10 small molecule compounds for inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Each compound must be tested in singlicate (n = 1) at seven different concentrations that cover a range of 0.1 uM to 100 uM.

b.) Provide a comprehensive report with the results of the experiments of each of the 10 compounds tested for inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. The report must include an IC50 determination for each of the above experiments.

4. CYP Inhibition Study - (NCATS_CYP60_03082019) Contractor will:

a.) Test each of 60 small molecule compounds for inhibition of CYP2C9, CYP2D6 and CYP3A4. Each compound must be tested in singlicate (n = 1) at seven different concentrations that cover a range of 0.1 uM to 100 uM.

b.) Provide a comprehensive report with the results of the experiments of each of the 60 compounds tested for inhibition of CYP2C9, CYP2D6 and CYP3A4. The report must include an IC50 determination for each of the above experiments.

Offerors submitting a response to this Small Business Sources Sought notice shall possess the ability to achieve the salient government essential features identified in this notice and provide documented evidence to be able to fully achieve the characteristicis of the subject requirement described herein.

Period of Performance
The contractor is expected to deliver results of work within two (2) months of the effective date of contract award and batch of material to analyze. The Government will send the contractor the material to synthesize after the effective date of contract award.

A Fixed-Price type of Purchase Order award not exceeding the Simplified Acquisition Threshold is anticipated for any contract resulting from this requirement. The anticipated award date is June 1, 2019.

Delivery/Warranty
Offerors should indicate an estimated delivery time in full after receipt of an order and any other training or warranty considerations applicable. Inspection and acceptance will be performed at NCATS located at 9800 Medical Center Drive, Rockville, MD 20852.

CAPABILITY STATEMENTS/INFORMATION SOUGHT
Interested parties are expected to review this notice to familiarize itself with the requirements of this project. Failure to do so will be at your firm's own risk.

Respondents must provide a capability statement with clear and convincing evidence of possessing the knowedge, skills, abilities and experience to successfully perform the requirements described in this announcement. Detailed prior experience in implementing similar requirements to the requirement described in this announcement shall be clearly delineated in any response provided. Technical experience may include, but is not limited to: Experience (> 5 years) in the testing of small molecule compounds as described in this announcement; evidence of published manuscripts in peer-reviewed journals of this or a related field; Access to all critical instrumentation necessary for this statement of work; Testing the aforementioned compounds in all the assays described above in.