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CXCR4 and MYC dual targeting in DLBCL
the patients. Among the 175 cytokines included in this array, we found that only CXCL12, IGFBP2 and IGFBP3 correlated significantly with high microvascular density (P<0.05) (Table 1), a parameter associated with an unfa- vorable prognosis in DLBCL.31,33 Additionally, high expression of CXCL12 correlated significantly with bone marrow involvement at diagnosis (P=0.02, data not shown), thus supporting a role for the CXCL12-CXCR4 axis in the progression of DLBCL.
IQS-01.01RS is a novel CXCR4 inhibitor with improved pharmacological properties
To evaluate the therapeutic potential of targeting CXCR4 in DLBCL, we took advantage of a novel family of CXCR4 inhibitors with improved pharmacodynamic properties and lower cardiotoxicity than the standard CXCR4 inhibitor AMD3100.34,35 Similarly to AMD3100, IQS-01.01 is a symmetric molecule with a central p-
phenylene group harboring two chiral carbons. The com- pound thus comports three stereoisomers, namely IQS- 01.01RR, IQS-01.01SS and IQS-01.01RS (Figure 1A). Nitrogen atoms on each site are intercalated in carbon chains at a similar distance as those of the cyclam in AMD3100 providing IQS-01.01 with positively charged nitrogen atoms at physiological pH which, as with AMD3100, will interact with the lateral chains of acidic amino acids of CXCR4, but with greater flexibility. We first assessed the inhibitory activity of IQS-01.01 (racemic mixture), and its three individually purified stereoiso- mers, using a CXCR4 antagonist screening study. AMD3100 was used as a reference drug. As shown in Figure 1B, the three stereoisomers had superior CXCR4 antagonist activity to that of AMD3100, with IQS- 01.01RS (see structure in Figure 1C) being the most potent agent. This compound led to a 181% inhibition of receptor activity, thus resembling an inverse receptor ago-
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C
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Figure 1. Design of a new potent inhibitor of CXCR4. (A) Skeletal structure of IQS-01.01. *chiral carbons. (B) Inhibition of CXCL12-mediated intracellular cAMP release was determined in the presence of a racemic mixture of IQS-01.01 and its three individually purified stereoisomers, using AMD3100 blocking activity as a reference control. (C) Ball-and-stick representation of IQS-01.01RS. * chiral carbons. (D) MTT assay showing superior antitumor effect of IQS-01.01RS compared to that of the IQS-01.01 racemic mixture after 48 h. The graph shows mean values obtained from three GCB-DLBCL cell lines (SUDHL6, SUDHL-16, and WSU-DLCL2) and three ABC-DLBCL cell lines (OCI-LY3, OCI-LY10 and SUDHL-2). (E) Inhibition of CXCL12-induced migration upon DLBCL cell treatment with a 100 mM dose of IQS- 01.01 racemic mixture or IQS-01.01RS. Mean values for the SUDHL-6 and OCI-LY3 cell lines are shown. *P<0.05, **P<0.01, ***P<0.001.
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