D1 SOW.pdf

STATEMENT OF WORK

(SOW)

GENERAL INFORMATION

Title of Project:

Testing of compounds in Cytochrome P450 (CYP) inhibition assays

Statement of Need and Purpose:

This requirement is for the testing of eighty (80) novel small molecule compounds in three (3) cytochrome P450 (CYP) Inhibition assays: CYP3A4 (midazolam substrate), CYP2C9, and

CYP2D6.

The testing of the compounds will provide critical information on CYP450 inhibitory activity in the compound series of small molecule IRAK4 / FLT3 kinase dual inhibitors and may facilitate further optimization and development of these IRAK4 / FLT3 inhibitor compounds as potential treatments for cancers such as Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes

(MDS).

Background Information and Objective:

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 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 small molecules as potential anticancer agents.

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 MDS and AML. Further optimization of the ADME (Absorption, Distribution, Metabolism, and Excretion) 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.

NCATS is currently synthesizing structurally novel analogs of NCGC00371481 that may show improved properties relative to previous analogs. In order to assess these analogs’ ADME properties, NCATS needs to test the compounds in assays that measure inhibition of CYP450 enzymes.

For a candidate compound to advance into clinical trials, it must display a wide range of acceptable properties. For instance, compounds must not potently inhibit major CYP450 enzymes such as CYP2C9, CYP2D6 and CYP3A4. These enzymes are responsible for oxidizing and metabolizing a majority of the toxins the body is exposed to, as well as for metabolizing many of the drug medications a patient may be taking. If a compound causes unwanted inhibition of these CYP450 enzymes, it could interfere with the metabolism and elimination of toxins from the body. The compound could also disrupt the metabolism of other drug medications a patient is taking, causing an undesired and potentially dangerous buildup of the unmetabolized drug in the body. This situation is referred to as a drug-drug interaction. The required testing of eighty (80) novel small molecule compounds in CYP450 inhibition assays will provide critical information on whether these compounds will not cause unwanted drug-drug interactions or interfere with the elimination of toxins from the body.

Period of Performance:

The anticipated period of performance is December 17, 2021 through December 16, 2022 (12-months).

SCOPE OF WORK

Requirements:

Independently and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, material, equipment, and facilities, not otherwise provided by the Government as needed to perform the following requirements:

1. The Contractor shall test each of the eighty (80) novel small molecule compounds in three CYP inhibition assays: CYP3A4 (midazolam substrate), CYP2C9, and CYP2D6.

Each compound shall be tested in 7 different doses, which will be determined by the Government at the time each batch is submitted. The 7 different doses shall be used to generate an IC50 curve.

2. The Contractor shall provide a comprehensive report for each of the four (4) batches of twenty (20) compounds (one report per batch of twenty compounds) in four CYP inhibition assays. The report must contain the following:

a. IC50 value; and

b. Curve or Plot used to calculate the IC50 value.

Government Responsibilities:

The Government will not furnish property, facilities, workspace, computers, or other equipment.

Performance of the services shall be on-site at the Contractor facility. The Government will have the responsibility to review and approve the reports and provide sufficient quantities of the lead compound in order for the contractor to perform the services described herein the SOW.

The Government anticipates, but does not guarantee, sending eighty (80) compounds in four (4) batches of twenty (20) compounds per batch, with the first batch being sent shortly after purchase order award and each subsequent batch being sent after the other, during the performance of the resultant firm fixed price purchase order with reasonable time for the contractor to perform the services during the 12-month period of performance.

Reporting Requirements:

As noted in the Requirements section above, the contractor will provide the data analysis and report for the contents of this statement of work. The data analysis and report shall be submitted within 60 days after receipt of the compounds and shall be submitted electronically to Scott Hoyt at scott.hoyt@nih.gov. The contractor will provide monthly updates on the progress of the project, or more often as appropriate.

Other Considerations:

Data Rights:

FAR Clause 52.227-14, Rights in Data-General (May 2014) is included in the solicitation and resultant award. Under 52.227-14(c)(1), the contractor must obtain approval from the contracting officer to assert copyright in any data first produced in performance of this contract and published in academic, technical or professional journals, symposia proceedings, or similar works. Under 52.227-14(d)(2), the contractor must obtain approval from the contracting officer to use, release to others, reproduce, distribute, or publish any data first produced or specifically used by the contractor in the performance of this contract.

In addition, the Contractor shall keep the results of the acquisition confidential.