Discovery of a Novel Microtubule Targeting Agent as an Adjuvant for Cancer Immunotherapy

Figure 1

Structure-activity relationship studies in 4H-chromene-3-carbonitriles. (a) HTS identification of the 4H-chromene-3-carbonitriles (insert) as a hit scaffold. We reanalyzed the data from two prior HTS for prolongation of NF-B activation 12 h after LPS versus ISRE activation 16 h after IFNα administration with a chemical library containing 1,778 compounds within this scaffold. The %activation values of each compound relative to the LPS and IFNα controls in the original HTS, respectively, are shown. (b) Structures for fused naphthalene, fused pyrazole, fused benzodioxolane, and fused dimethylaminobenzene scaffolds. (c) SEAP production by the THP-1-Blue NF-B reporter cell line stimulated with 5 μM of each compound in the absence versus the presence of 10 ng/mL LPS. Each symbol indicates the means ± SEM for triplicates of individual compounds. (d) IL-12 secretion by BMDCs stimulated with compounds in the presence of 0.5 ng/mL LPS significantly correlated with SEAP production measured by THP-1-Blue NF-B reporter cells measured in triplicate. The dotted line indicates the regression line (Spearman r=0.81, P<0.0001, n=23). Each symbol indicates the means ± SEM for triplicates of individual compounds.

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