# Scientific Core - Compound Optimization and Prioritization.

> **NIH NIH U19** · GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT · 2020 · $2,128,141

## Abstract

The Specific Aim of Core A is to provide an integrated structure-guided lead identification and optimization
effort, in collaboration with Projects 1–4 and Core B, with the ultimate objective of delivering advanced leads for
entry into translational studies comprising early development (Core C) toward an Investigational New Drug IND
filing, and preclinical regimen development and pharmacokinetic/pharmacodynamic (PKPD) studies (Project 4).
This will be accomplished through two Activities: (1) Lead Identification, to identify a lead compound within a
series, with demonstrated efficacy in Mycobacterium tuberculosis (Mtb)-infected mice, that is sufficiently well
characterized to allow development of a clear lead optimization plan, and (2) Lead Optimization and Compound
Prioritization, to optimize the lead(s) identified in Activity 1 to meet the criteria required to initiate non-GLP safety
studies (in Core C), and proceed to regimen development in Project 4. To conduct these activities, Core A will
provide capabilities including medicinal chemistry (design and synthesis); structural biology; computational
chemistry; in vitro and in vivo absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic
(PK) studies; in vitro safety assays; preliminary toxicity studies, and scale-up synthesis. These capabilities will
support selection of compounds from Projects 1–3, for further progression. together with evaluations of
antituberculosis activity through Core B. The Core will innovate by providing state-of-the-art structural and
computational approaches in designing small molecules and peptides and leverage the latest developments in
understanding of oral bioavailability of large peptides and peptidomimetics. Effective direction and successful
implementation of these capabilities and processes is critical to the overall goals of the CETR, which include
selection of drug candidates against three drug targets, from Projects 1–3. Core A will be led by TB Alliance,
which is ideally suited to the task, with extensive experience in drug discovery and development and a track
record of success: the Core A PI, Dr. Upton, and the key personnel, have collectively over 100 years of experience
within the pharmaceutical industry and TB Alliance in drug discovery and development. Over the last two years,
the team has advanced four projects into IND-enabling studies and filed three INDs, with two more expected in
2018. The team also manages a mature portfolio of lead Identification and lead optimization projects. The Core
will operate using the successful virtual R&D model of TB Alliance: All activities will be carried out with partners
and contract research organizations (CROs). For each series, a unique, tailored program of studies will be
developed where partners and CROs will be selected based on need, cost, quality, and timing, leveraging the
expertise and specializations of the named organizations that will participate (such as Proteros and Schrodinger)...

## Key facts

- **NIH application ID:** 9904477
- **Project number:** 5U19AI142735-02
- **Recipient organization:** GLOBAL ALLIANCE FOR TB DRUG DEVELOPMENT
- **Principal Investigator:** Anna Upton
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,128,141
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904477

## Citation

> US National Institutes of Health, RePORTER application 9904477, Scientific Core - Compound Optimization and Prioritization. (5U19AI142735-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904477. Licensed CC0.

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