D 75N95020Q00023_Statement of Work.pdf

Version 11-30-2016-1 FAR Part 11—Describing Agency Needs

STATEMENT OF WORK

(SOW)

GENERAL INFORMATION

Title of Project:

Kinase Assays: Testing 15 Novel Small Molecule Compounds using the Kinase HotSpot Assay Platform

Statement of Need and Purpose:

NCATS requires the testing of 15 novel small molecule compounds using the Kinast HotSpot Assay Platform. This testing is for two (2) separate studies and will be performed in two separate assays:

1. The testing of ten (10) novel small molecule compounds for inhibition of a set of 50 wild-type kinase enzymes. This testing will inform on kinase inhibitory activity in our compound series, and will facilitate further optimization and development of these IRAK4 / FLT3 inhibitor compounds as potential treatments.

2. The testing of five (5) novel small molecule compounds for inhibition of a set of 374 wild-type kinase enzymes. This testing will inform on kinase inhibitory activity in our compound series, and will facilitate further optimization and development of these IRAK4 / FLT3 inhibitor compounds as potential treatments for cancers such as AML and 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 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 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 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.

We are currently synthesizing structurally novel analogs of NCGC00371481 that may show improved properties relative to previous analogs. In order to assess these analogs’ selectivity, we need to test them against structurally-related kinase enzymes. The full ‘kinome’ is known to contain >400 wild-type

Solicitation No. 75N95020Q00023 kinase enzymes, and these are all closely related in terms of protein structure and function. As such, compounds that inhibit our intended targets (IRAK1, IRAK4 and FLT3) will likely also inhibit many other closely related kinase enzymes as unintended off-targets. Such activity – termed ‘off-target inhibition’ – can cause undesired safety-related side-effects when compounds are dosed in preclinical species, or in the clinic. In order to minimize the chances of unwanted side-effects, we need to minimize the inhibition of kinase off-targets.

As a cost-effective way of estimating inhibition of the full kinome, we have recently devised kinome mini-panels, which are representative sets of kinases that are meant to predict inhibitory activity against the full kinome. We believe that a testing against a representative set of 50 kinase enzymes can be predictive of the inhibitory activity that a compound will display against the full kinome of >400 kinases.

Testing against a representative set of 50 is less expensive than testing against a full set of >400, and thus may be used in early rounds of research as a resource-sparing way of estimating kinase selectivity.

Testing of 10 small molecule compounds for inhibition of a representative set of 50 wild-type kinase enzymes will allow a determination of their ‘off-target’ activity. That data will facilitate the further prioritization and optimization of compounds in this series for therapeutic use against a variety of cancers, including MDS and AML.

Prior analogs in this series were tested against IRAK1, IRAK4, FLT3, and other relevant kinase enzymes using Kinase HotSpot assay technology. To ensure consistency in the data and an ‘apples-to-apples’ comparison, the current set of compounds should also be tested using Kinase HotSpot assay technology.

Period of Performance:

The period of performance is 12 months from the date of contract award.

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 listed in the Government Responsibilities section below, as needed to perform the following requirements:

1. Test ten (10) novel small molecule compounds for inhibition of a set of 50 wild-type kinase enzymes.

The contractor will:

a. Test each of the 10 small molecule compounds for inhibitory activity against a set of 50 wild-type kinase enzymes, using the Kinase HotSpot assay platform.

i. Compounds will be tested in 10 different doses, which will be determined by the Government at the time each batch is submitted.

ii. The 10 different doses will be used to generate an IC50 curve.

iii. The Government anticipates sending the 10 compounds in two (2) separate batches containing five (5) compounds each. The Government anticipates sending one batch in March 2020 and one batch in November 2020.

b. Provide two comprehensive reports with the results of each of the 10 compounds against the 50 wild-type kinases; one report for each batch of compounds.

2. Test five (5) novel small molecule compounds for inhibition of a set of 374 wild-type kinase enzymes. The contractor will:

a. Test each of the five (5) small molecule compopunds for for inhibitory activity against a set of 374 wild-type kinase enzymes, using the Kinase HotSpot assay platform.

i. Compounds will be tested in 10 different doses, which will be determined by the Government at the time each batch is submitted.

ii. The 10 different doses will be used to generate an IC50 curve.

b. Provide a comprehensive report with the results of each of the five (5) compounds against the 374 wild-type kinases.

GOVERNMENT RESPONSIBILITIES

The Government will not furnish property, facilities, workspace, computers, or other equipment. The contractor will not use federal facilities. The Government will provide sufficient quantities of the lead compounds in order for the contractor to accomplish the requirements described above. The Government will have the responsibility to review and approve the comprehensive reports.

DELIVERY OR DELIVERABLES

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.

REPORTING REQUIREMENTS

The contractor will provide monthly updates on the progress of the project, or more often as appropriate. The updates shall be provided electronically to Scott Hoyt at scott.hoyt@nih.gov.

OTHER CONSIDERATIONS

Data Rights:

FAR 52.227-17, Rights in Data – Special Works

Section 508—Electronic and Information Technology Standards:

The contractor will not be involved in EIT Standards.

mailto:scott.hoyt@nih.gov mailto:scott.hoyt@nih.gov

Publications and Publicity:

The contractor will not publish results of the work.

Confidentiality of Information:

The contractor will keep the results of the acquisition confidential.