Small Molecule Inhibitors of CXCR4

Debnath, Bikash; Xu, Shili; Grande, Fedora; Garofalo, Antonio; Neamati, Nouri

doi:10.7150/thno.5376

Cited by 242 publications

(214 citation statements)

References 115 publications

(153 reference statements)

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“…Accordingly, CXCR4 overexpression has been identified as an adverse prognostic factor in some malignancies, including non-small cell lung cancer (NSCLC) and breast cancer (6,15). Because of its critical role in cancer, CXCR4 has been designated a potential therapeutic target and several CXCR4 inhibitors have been developed, with some of them reaching clinical trials (2,16).…”

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confidence: 99%

First Experience with Chemokine Receptor CXCR4–Targeted PET Imaging of Patients with Solid Cancers

et al. 2016

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CXCR4 is a chemokine receptor that is overexpressed in various human cancers and is involved in tumor metastasis. The aim of this proof-of-concept study was to evaluate a novel CXCR4-targeted PET probe in patients with solid cancers with reported in vitro evidence of CXCR4 overexpression and to estimate its potential diagnostic value. Methods: Twenty-one patients with histologically proven pancreatic cancer, laryngeal cancer, non-small cell lung cancer, prostate cancer, melanoma, breast cancer, hepatocellular carcinoma, glioblastoma, sarcoma, or cancer of unknown primary underwent PET imaging using the novel CXCR4 nuclear probe 68 Ga-pentixafor. The SUV max of the liver, spleen, and bone marrow was measured to determine physiologic tracer distribution. For evaluation of tracer accumulation in solid cancers, SUV max and tumor-tobackground (T/B) ratios were determined in a total of 43 malignant lesions, including 8 primary tumors, 3 locally recurrent tumors, and 32 metastases. When available, the SUV max of malignant lesions was compared with the corresponding SUV max measured in routine 18 F-FDG PET. Results: Moderate tracer accumulation was detectable in the liver, bone marrow, and spleen, with a mean SUV max of 3.1, 3.7, and 5.6, respectively. By visual interpretation criteria, 9 of 11 primary and locally recurrent tumors were detectable, exhibiting a mean SUV max of 4.7 (range, 2.1-10.9) and a mean T/B ratio of 2.9. Twenty of 32 evaluated metastases were visually detectable (mean SUV max , 4.5 [range, 3.2-13.8]; mean T/B ratio, 2.8). The highest signal was detected in a patient with non-small cell lung cancer (SUV max , 10.9; T/B ratio, 8.4) and a patient with cancer of unknown primary (SUV max , 13.8; T/B ratio, 8.1). Compared with 18 F-FDG PET, which was additionally performed in 10 patients, 68 Gapentixafor PET had a lower SUV max in all measured malignant lesions. Conclusion: On the basis of these first observations in a small and heterogeneous patient cohort, the in vitro CXCR4 expression profile of solid cancers and metastases described in the previous literature does not seem to sufficiently depict the in vivo distribution revealed by CXCR4-targeted PET. Moreover, the detectability of solid cancers seems to be generally lower for 68 Ga-pentixafor than for 18 F-FDG PET.

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confidence: 99%

First Experience with Chemokine Receptor CXCR4–Targeted PET Imaging of Patients with Solid Cancers

et al. 2016

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“…Deregulation of CXCR4 expression in multiple human cancers, its role in hematopoietic stem cell migration, and the utilization of CXCR4 by HIV-1 for T-cell entry, make this receptor an increasingly important therapeutic target (1). One FDA-approved drug against CXCR4 is currently on the market (Mozobil, for hematopoietic stem cell mobilization), and multiple additional drugs against this target are in development for oncology and other indications (2).…”

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confidence: 99%

Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices

Wescott

Kufareva

Paes

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

115

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The atomic-level mechanisms by which G protein-coupled receptors (GPCRs) transmit extracellular ligand binding events through their transmembrane helices to activate intracellular G proteins remain unclear. Using a comprehensive library of mutations covering all 352 residues of the GPCR CXC chemokine receptor 4 (CXCR4), we identified 41 amino acids that are required for signaling induced by the chemokine ligand CXCL12 (stromal cell-derived factor 1). CXCR4 variants with each of these mutations do not signal properly but remain folded, based on receptor surface trafficking, reactivity to conformationally sensitive monoclonal antibodies, and ligand binding. When visualized on the structure of CXCR4, the majority of these residues form a continuous intramolecular signaling chain through the transmembrane helices; this chain connects chemokine binding residues on the extracellular side of CXCR4 to G proteincoupling residues on its intracellular side. Integrated into a cohesive model of signal transmission, these CXCR4 residues cluster into five functional groups that mediate (i) chemokine engagement, (ii) signal initiation, (iii) signal propagation, (iv) microswitch activation, and (v) G protein coupling. Propagation of the signal passes through a "hydrophobic bridge" on helix VI that coordinates with nearly every known GPCR signaling motif. Our results agree with known conserved mechanisms of GPCR activation and significantly expand on understanding the structural principles of CXCR4 signaling.T he CXC chemokine receptor 4 (CXCR4) belongs to the G protein-coupled receptor (GPCR) superfamily of proteins, the largest class of integral membrane proteins encoded in the human genome, comprising greater than 30% of current drug targets. Deregulation of CXCR4 expression in multiple human cancers, its role in hematopoietic stem cell migration, and the utilization of CXCR4 by HIV-1 for T-cell entry, make this receptor an increasingly important therapeutic target (1). One FDA-approved drug against CXCR4 is currently on the market (Mozobil, for hematopoietic stem cell mobilization), and multiple additional drugs against this target are in development for oncology and other indications (2).The crystal structures of class A GPCR superfamily members in their active and inactive conformations (reviewed in refs. 3 and 4) provide unprecedented insight into the structural basis of ligand binding, G protein coupling, and activation of GPCRs via rearrangements of transmembrane (TM) helices. GPCR helices V and VI in particular, and in some cases III and VII, are known to undergo significant conformational changes upon activation (5-7). However, static images alone have not been able to explain the residue-level mechanisms underlying the dynamic helical shifts that mediate GPCR signal transduction. Additionally, only inactive state structures have been solved for CXCR4 and most other GPCRs (8,9). Over the last two decades, extensive mutagenesis studies of GPCRs in general [collectively describing >8,000 mutations (gpcrdb.org)] and of CX...

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“…The successful development of inhibitors against CXCR4/ SDF-1 interactions based on small molecules, peptides and antibodies in clinical and pre-clinical studies for HSC mobilization (Reviewed in [39,40]) has prompted the development of other classes of inhibitors with greater pharmacokinetic stability and superior in vivo efficacy. New structural classes of CXCR4/SDF-1 inhibitors may also assist in illuminating new mechanisms into HSC mobilization owing to the complexity of the CXCR4/ SDF-1 axis (Reviewed in [41]).…”

Section: Novel Modulators Of Cxcr4/sdf-1mentioning

confidence: 99%