# Sulfotyrosine-guided discovery of small molecule chemokine inhibitors

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2021 · $305,720

## Abstract

Project Summary/Abstract
The goal of this project is the development of an innovative platform for discovery of
small molecule chemokine inhibitors. Chemokines direct cell migration primarily by
binding and activating a family of G protein-coupled receptors that are post-
translationally modified by tyrosine sulfation. Sulfation is required for chemokine
function, suggesting that receptor sulfotyrosines participate directly in specific binding of
the chemokine ligand. We first revealed the molecular basis for sulfotyrosine recognition
in the chemokine family by solving the NMR structure of a complex between the
chemokine SDF1/CXCL12 and a sulfotyrosine-containing fragment of its receptor
CXCR4. The N-terminal extracellular domain of CXCR4 contains three potential sulfation
sites, and each sulfotyrosine occupies a unique cleft on the CXC12 surface. In the initial
funding period we showed that sulfotyrosine recognition sites are essential for high
affinity receptor binding and can be targeted for inhibition using small molecules
directed at the chemokine ligand. We also discovered an unprecedented example of
autoinhibition in the chemokine family by an intrinsically disordered region of CCL21. In
this renewal application, we propose to identify small molecule ligands of the three main
pro-metastatic chemokines. We will screen for chemical fragments that bind the
sulfotyrosine-recognition sites of CXCL12, CCL19 and CCL21and optimize them as
competitive inhibitors of receptor binding that block cancer cell migration (aim 1),
develop a chemical inducer of dimerization that converts endogenous CXCL12 into an
inhibitory biased agonist (aim 2), and screen for molecules that bind and stabilize the
autoinhibited form of CCL21 (aim 3). Structure-based drug discovery guided by
sulfotyrosine recognition is a conceptual advance that can be applied to most of the 50
members of the chemokine family and other complexes that require this protein
modification to function in the extracellular space. New cancer treatments that emerge
from application of this strategy will have a major impact on human health.

## Key facts

- **NIH application ID:** 10104512
- **Project number:** 5R01GM097381-08
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Brian F Volkman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $305,720
- **Award type:** 5
- **Project period:** 2011-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104512

## Citation

> US National Institutes of Health, RePORTER application 10104512, Sulfotyrosine-guided discovery of small molecule chemokine inhibitors (5R01GM097381-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10104512. Licensed CC0.

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