# Stereoisomeric chemical probes for targeting undruggable oncoproteins

> **NIH NIH F32** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $67,582

## Abstract

Project Summary
 Medicinal chemistry saw a paradigm shift in the 1980’s when natural product isolation and phenotypic
screens were largely replaced by combinatorial chemistry and structure-based drug design. This transformation
was prompted by key advances in molecular biology, structural biology, and synthetic chemistry. For example,
the advent of reliable, high yielding coupling chemistries (e.g., peptide coupling, palladium-mediated cross
couplings) and a set of concise rules (i.e., Lipinski’s rules) revolutionized the efficiency of medicinal chemistry.
Although this expedited the rate of production and size of small-molecule libraries, it was not without a cost.
Modern chemical libraries are overpopulated with flat, nondescript compounds that contain fewer than one
stereocenter per member and ca. 20% sp3 content. These properties are favorable for engaging deep binding
pockets in proteins; however, they are ill-equipped for the shallower surfaces involved in macromolecular (e.g.,
protein-protein, protein-oligonucleotide) interactions. On the other hand, natural products and their derivatives
have proven capable of binding a wide range of challenging targets, including those that are considered
“undruggable” due to their skeletal and stereochemical complexity”, and consequently represent the majority of
FDA-approved drugs. Diversity-oriented synthesis (DOS), biology-oriented synthesis, and complexity-to-
diversity have emerged as organic chemistry strategies that embrace the power of natural product complexity to
establish diverse chemical libraries emphasizing densely functionalized, entropically constrained, and
stereochemically defined cores. Concurrently, chemical proteomic platforms, such as activity-based protein
profiling, are providing a global approach to map the interactions between small molecules and proteins directly
in native biological systems for the first time. Chemical proteomic efforts have radically expanded the number of
proteins and ligandable sites that can be targeted by small molecules, including many examples that previously
lacked chemical probes. This proposal aims to integrate the principles of DOS, covalent chemistry, and chemical
proteomics to create highly innovative small-molecule libraries of stereochemical and skeletal complexity and to
use these libraries to discover the first selective and cell-active chemical probes for diverse oncoprotein targets.
In Specific Aim 1, we will optimize acrylamide ligands that show stereoselective engagement of key cancer
targets, including oncogenic transcription factors and nucleotide exchange factors. Advanced compounds, either
as direct functional antagonists or bifunctional degraders, will be used to suppress the growth of cancer cells
that have been shown to strongly and selectively depend on these oncoproteins. In Specific Aim 2, we will expand
our stereoisomeric library to interrogate new three-dimensional chemical space. Specifically, we will establish a
library of e...

## Key facts

- **NIH application ID:** 10547740
- **Project number:** 5F32CA265211-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Christopher John Reinhardt
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10547740

## Citation

> US National Institutes of Health, RePORTER application 10547740, Stereoisomeric chemical probes for targeting undruggable oncoproteins (5F32CA265211-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10547740. Licensed CC0.

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