D.CSS_Attach1-SOW.pdf

Title of Project:

Statement of Need and Purpose:

Background Information and Objective:

Statement of Work for Services (SOW)

General Information:

Testing of Compounds for Kinase Inhibition

NCATS requires the testing of 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 three hundred (300) novel small molecule compounds for inhibition of a set of 3 wild-type kinase enzymes. This testing will inform on kinase inhibitory activity in NCATS’ 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.

2. 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 selectivity in NCATS’ 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.

The mission of the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) is to catalyze the generation of innovative methods and technologies that will enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of human diseases and conditions.

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.

NCATS is currently synthesizing structurally novel analogs of NCGC00371481 that may show improved properties relative to previous analogs. In order to assess these analogs’ on-target potency against targets like IRAK4 and FLT3, NCATS needs to test them for activity vs. a panel of 3 wild-type kinases. Testing a set of 300 small molecule compounds vs. 3 wild-type kinases will allow optimization of on-target potency in this compound series.

In addition to assessing their potency in the panel of 3 on-target kinases, NCATS also needs to assess these analogs’ selectivity by testing them against structurally-related kinase enzymes. The full ‘kinome’ is known to contain >400 wild-type 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, NCATS needs to minimize the inhibition of kinase off-targets.

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Period of Performance:

General Requirements:

Specific Requirements:

As a cost-effective way of estimating inhibition of the full kinome, NCATS recently devised kinome mini-panels, which are representative sets of kinases that are meant to predict inhibitory activity against the full kinome. NCATS believes that 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 cost-effective 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.

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

Scope of Work:

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 Statement of Work below:

1. Test three hundred (300) novel small molecule compounds for inhibition of a set of 3 wild-type kinase enzymes. The contractor will:

a. Test each of the 300 small molecule compounds for inhibitory activity against a set of 3 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 300 compounds in ten batches of at least 30 compounds per batch.

b. Provide ten comprehensive reports with the results of each of the 300 compounds against the 3 wild-type kinases; one report for each of the ten batches of compounds.

2. 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 batches of 5 compounds per batch.

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

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Travel:

Key Personnel:

Information System Security Plan:

Data Rights:

Section 508:

Confidentiality of Information:

Level of Effort:

Not applicable.

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:

No travel is required.

None specified.

Not applicable.

The clause at FAR 52.227-14, Rights in Data-General, shall be incorporated by reference to this contract.

Not applicable.

The contractor shall not publish results of the work.

All data and information generated under this contract and or furnished to the contractor is confidential information and shall not be disclosed by the contractor without the prior written consent of the Government.

Publications and Publicity:

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