Compound testing for inhibition of wild-type kinase enzymes and block of cardiac ion channels

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 small molecules as potential anti-cancer 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.

Scientists are NCATS are currently synthesizing structurally-novel analogs of NCGC00371481 that may show improved properties relative to previously syntesized 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 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, and thus need to test for inhibition of the full kinome panel.

To promote efficiency in estimating inhibition of the full kinome, NCATS has recently devised kinome mini-panels, which are representative sets of kinases that are meant to predict inhibitory activity against the full kinome. It is believed 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 more efficient than testing against a full set of >400 kinases and thus is more desired to use in early rounds of research as a more ideal method 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. Testing of 5 small molecule compounds for inhibition of the full kinome panel of 374 wild-type kinase enzymes will allow a determination of their 'off-target' activity.

Prior analogs in this series were tested against IRAK1, IRAK4, FLT3, and other relevant kinase enzymes using Kinase HotSpot assay technology. The current set of compounds need to be tested using Kinase HotSpot assay technology, or its equal, to ensure consistency of data and produce consistent results to prior and existing research at NCATS.

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). Candidate compounds also need to be free of various types of cardiotoxicity, for instance any undesired effects on heart rate (bradycardia or tachycardia, abnormally slow or fast heart rate), blood pressure (too high or too low), or the potentially lethal condition known as 'torsades de pointes', which results from prolongation of the cardiac QT interval. These undesired cardiotoxicities can often be traced directly to block of a key ion channel: hERG for QT prolongation, Nav1.5 for effects on heart rate, or Cav1.2 for effects on blood pressure. Preclinical testing of candidate drug compounds for block of these important ion channels is a widely-used strategy for the early identification of potential sources of cardiotoxicity. Optimization of compounds within a series so that key compounds do not block these channels is typically a prerequisite for identifying a drug candidate that can advance into human clinical trials.

A variety of different biological assay formats are available to test ion channel block. These include binding assays, functional assays, and a specific type of functional assay known as patch-clamp. Of these, patch-clamp assays shall be used in testing of these compounds. Such assays shall be conducted in automated formats providing high-quality data in testing compounds. The testing of an initial set of 30 small molecule compounds for block of hERG, Nav1.5 and Cav1.2 in automated patch-clamp assays will allow a determination of the compounds' activity against these targets, and will help to identify any unwanted properties that would need to be removed in subsequent, more advanced compounds.

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:

1. 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 the 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. 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 the 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.

3. Initial testing of 30 small molecule compounds for block of the important cardiac-related ion channels hERG, Cav1.2 and Nav1.5. These drug molecule compounds are being evaluated for dual purpose in the IRAK4-FLT3 kinase program. Testing of the compounds for their capacity to block hERG, Cav1.2 and Nav1.5 will help to identify potential souces of cardiotoxicity, and alert any such issues that would need to be solved in order for drug candidates to advance into human clinical testing.

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:

Task 1:
1. Perform experiments using the Kinase HotSpot assay platform testing each of 10 small molecule compounds for inhibitory activity against at least 50 wild-type kinase enzymes.
2. Provide a comprehensive report with the results of the 10-dose IC50 singlet titrations of each of the 10 compounds against the 50 wild-type kinases.

Task 2:
1. Perform experiments using the Kinase HotSpot assay platform testing each of 5 small molecule compounds for inhibitory activity against at least 374 wild-type kinase enzymes.
2. Provide a comprehensive report with the results of the 10-dose IC50 singlet titrations of each of the 5 compounds against the 374 wild-type kinases.

Task 3:
1. Perform single-dose (single concentration) experiments in triplicate, testing each of 30 small molecule compounds in automated patch-clamp assays for block of hERG, Nav1.5 and Cav1.2.
2. Provide a comprehensive report with the results of the experiments of each of the 30 compounds against hERG, Nav1.5 and Cav1.2.

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 tasks 1 and 2 within 6 months of the effective date of contract award and final batch of material to analyze. The contractor is expected to deliver results of task 3 within 2 months of receipt of material for analysis by the Government. 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 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 must be clearly delineated in any response provided. Technical experience can include, but is not limited to: Experience (> 5 years) in the testing of small molecule compounds for kinase inhibitory activity using the Kinase HotSpot assay platform; Access to all critical instrumentation necessary for this statement of work; Testing the aforementioned compounds in all the assays described above in.