# Target enablement

> **NIH NIH U19** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $6,545,783

## Abstract

The success of the Center's drug discovery programs relies on being experimentally fully enabled to support
compound development. In the Target Enablement project, we will develop and validate the experimental
procedures by producing "Target Enabling Packages" (TEPs). These comprise a set of experimental protocols
and outputs that generate the rapid, reliable, full-spectrum readouts that underpin the acceleration of the designmake-
test-analyze (DMTA) cycles. TEPs are highly effective enablers of medicinal chemistry on targets and
targeting modalities where they can be achieved; nevertheless, frequently they remain incomplete, since they
require great effort to assemble from literature and/or trial-and-error experiments; and determined medicinal
chemists might manage to progress compound series anyway. However, this conceals the real and opportunity
costs of doing so, which includes the synthesis of unnecessary compounds, pursuit of dead-end hypotheses,
and poor models of the data. In the Target Enablement project, we propose to generate next generation TEPs
that include the reagents and protocols for generating biochemically-behaved, well-crystallizing protein, 3D
interaction maps of the binding site(s) from a crystal-based fragment screen, biochemical and biophysical assays
and persuasive hit compounds, displaying consistent low micromolar affinity, activity and binding pose,
rationalizable across a set of analogues. We will deliver TEPs that are rigorous, effective, and reproducible, by
(a) contracting in the established, systematic workflow developed since 2015 at the University of Oxford, and (b)
implementing and hardening of recent innovations and new technologies, including methods developed in the
wake of the COVID Moonshot and other pandemic-related work. The specific goal of Project 2 is thus to generate
next generation TEPs for 10 targets, to drive rapid hit-to-lead progression in Project 3 and thence validation of
the antiviral hypothesis by virology and chemical biology. The goal is spread over 4 Aims, with Aim 1 establishing
biochemical and crystal structure tractability of all novel targets identified in Project 1. Aim 2 builds on the outputs
from Aim 1 and develops the robust crystallization protocols, and orthogonal assays for biochemical activity and
biophysical affinity. Aim 3 entails the completion and analyses of the crystallographic fragment screens. Aim 4
finalizes TEPs by validating assays and binding pose with hit compounds derived from observed fragments. In
summary, Project 2 combines an established workflow with recent innovations to deliver TEPs that are rigorous,
effective and reproducible, providing the foundations for the far-reaching innovations of Project 3 thus ensuring
ASAP can deliver on time and on budget. Moreover, TEPs will be promptly published to enable parallel efforts
beyond ASAP and increase the overall chances of achieving pandemic preparedness. The project will be
delivered by the same team at Diamon...

## Key facts

- **NIH application ID:** 10513872
- **Project number:** 1U19AI171399-01
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** John Damon Chodera
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $6,545,783
- **Award type:** 1
- **Project period:** 2022-05-16 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513872

## Citation

> US National Institutes of Health, RePORTER application 10513872, Target enablement (1U19AI171399-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10513872. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*