Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction

Joshua J. Ziarek, Yan Liu, Emmanuel Smith, Guolin Zhang, Francis C. Peterson, Jun Chen, Yongping Yu, Yu Chen, Brian F. Volkman, Rongshi Li

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The chemokine CXCL12 and its G protein-coupled receptor (GPCR) CXCR4 are high-priority clinical targets because of their involvement in metastatic cancers (also implicated in autoimmune disease and cardiovascular disease). Because chemokines interact with two distinct sites to bind and activate their receptors, both the GPCRs and chemokines are potential targets for small molecule inhibition. A number of chemokines have been validated as targets for drug devel- opment, but virtually all drug discovery efforts focus on the GPCRs. However, all CXCR4 receptor antagonists with the exception of MSX-122 have failed in clinical trials due to unmanageable toxicities, emphasizing the need for alternative strategies to interfere with CXCL12/CXCR4-guided metastatic homing. Although targeting the relatively featureless sur- face of CXCL12 was presumed to be challenging, focusing efforts at the sulfotyrosine (sY) binding pockets proved suc- cessful for procuring initial hits. Using a hybrid structure-based in silico/NMR screening strategy, we recently identified a ligand that occludes the receptor recognition site. From this initial hit, we designed a small fragment library containing only nine tetrazole derivatives using a fragment-based and bioisostere approach to target the sY binding sites of CXCL12. Compound binding modes and affinities were studied by 2D NMR spectroscopy, X-ray crystallography, molecular dock- ing and cell-based functional assays. Our results demonstrate that the sY binding sites are conducive to the development of high affinity inhibitors with better ligand efficiency (LE) than typical protein-protein interaction inhibitors (LE 0.24). Our novel tetrazole-based fragment 18 was identified to bind the sY21 site with a Kd of 24 μM (LE = 0.30). Optimization of 18 yielded compound 25 which specifically inhibits CXCL12-induced migration with an improvement in potency over the initial hit 9. The fragment from this library that exhibited the highest affinity and ligand efficiency (11: Kd = 13 μM, LE = 0.33) may serve as a starting point for development of inhibitors targeting the sY12 site.

Original languageEnglish (US)
Article numberA003
Pages (from-to)2727-2740
Number of pages14
JournalCurrent Topics in Medicinal Chemistry
Volume12
Issue number24
StatePublished - Jan 1 2012

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Ligands
Chemokines
Binding Sites
CXCR4 Receptors
Chemokine CXCL12
X Ray Crystallography
Drug Discovery
G-Protein-Coupled Receptors
Computer Simulation
Autoimmune Diseases
Libraries
Proteins
Cardiovascular Diseases
Magnetic Resonance Spectroscopy
Clinical Trials
Pharmaceutical Preparations
tyrosine O-sulfate
Neoplasms
1H-tetrazole

Keywords

  • CXCL12/CXCR4 inhibitors
  • Chemokines
  • Fragment-based and structureguided drug design
  • Metastasis
  • Protein-protein interaction

ASJC Scopus subject areas

  • Drug Discovery

Cite this

Ziarek, J. J., Liu, Y., Smith, E., Zhang, G., Peterson, F. C., Chen, J., ... Li, R. (2012). Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction. Current Topics in Medicinal Chemistry, 12(24), 2727-2740. [A003].

Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction. / Ziarek, Joshua J.; Liu, Yan; Smith, Emmanuel; Zhang, Guolin; Peterson, Francis C.; Chen, Jun; Yu, Yongping; Chen, Yu; Volkman, Brian F.; Li, Rongshi.

In: Current Topics in Medicinal Chemistry, Vol. 12, No. 24, A003, 01.01.2012, p. 2727-2740.

Research output: Contribution to journalArticle

Ziarek, JJ, Liu, Y, Smith, E, Zhang, G, Peterson, FC, Chen, J, Yu, Y, Chen, Y, Volkman, BF & Li, R 2012, 'Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction', Current Topics in Medicinal Chemistry, vol. 12, no. 24, A003, pp. 2727-2740.
Ziarek JJ, Liu Y, Smith E, Zhang G, Peterson FC, Chen J et al. Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction. Current Topics in Medicinal Chemistry. 2012 Jan 1;12(24):2727-2740. A003.
Ziarek, Joshua J. ; Liu, Yan ; Smith, Emmanuel ; Zhang, Guolin ; Peterson, Francis C. ; Chen, Jun ; Yu, Yongping ; Chen, Yu ; Volkman, Brian F. ; Li, Rongshi. / Fragment-based optimization of small molecule CXCL12 inhibitors for antagonizing the CXCL12/CXCR4 interaction. In: Current Topics in Medicinal Chemistry. 2012 ; Vol. 12, No. 24. pp. 2727-2740.
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