Discovery of CC-930, an orally active anti-fibrotic JNK inhibitor.

In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.

Natural selection of FLT1 alleles and their association with malaria resistance in utero.

Placental malaria (PM) caused by Plasmodium falciparum contributes significantly to infant mortality in sub-Saharan Africa and is associated with pregnancy loss. We hypothesized that fetal genes that modify PM would be associated with fetal fitness. During PM, placental trophoblasts produce soluble fms-like tyrosine kinase 1 (sFlt1), also known as soluble VEGF receptor 1, an angiogenesis inhibitor associated with preeclampsia. Here we present a study examining the genotype of the fms-related tyrosine kinase 1 (FLT1) 3' UTR in Tanzanian mother-infant pairs. First-time mothers suffer the most PM, and newborn FLT1 genotype distribution differed by birth order, with newborns of first-time mothers outside of Hardy-Weinberg equilibrium (HWE) during peak PM season. Among first-time but not other mothers, maternal FLT1 genotype was associated with a history of prior pregnancy loss. During PM, newborn FLT1 genotype was associated with low birth weight and placental inflammatory gene expression. FLT1 genotype was also associated with Flt1 levels among study subjects and in vitro. Thus, FLT1 variants confer fetal fitness in utero and are associated with the maternal immune response during PM. This indicates that FLT1 is under natural selection in a malaria endemic area and that human exposure to malaria can influence the evolutionary genetics of the maternal-fetal relationship.

Genome-wide expression analysis of placental malaria reveals features of lymphoid neogenesis during chronic infection.

Chronic inflammation during placental malaria (PM) is most frequent in first time mothers and is associated with poor maternal and fetal outcomes. In the first genome-wide analysis of the local human response to sequestered malaria parasites, we identified genes associated with chronic PM and then localized the corresponding proteins and immune cell subsets in placental cryosections. B cell-related genes were among the most highly up-regulated transcripts in inflamed tissue. The B cell chemoattractant CXCL13 was up-regulated >1,000-fold, and B cell-activating factor was also detected. Both proteins were expressed by intervillous macrophages. Ig L and H chain transcription increased significantly, and heavy depositions of IgG3 and IgM were observed in intervillous spaces. The B cell phenotype was heterogeneous, including naive (CD27-negative), mature (CD138-positive), and cycling (Ki-67-positive) cells. B cells expressed T-bet but not Bcl-6, suggesting T cell-independent activation without germinal center formation. Genes for the Fc binding proteins FcgammaRIa, FcgammaRIIIa, and C1q were highly up-regulated, and the proteins localized to intervillous macrophages. Birth weight was inversely correlated with transcript levels of CXCL13, IgG H chain, and IgM H chain. The iron regulatory peptide hepcidin was also expressed but was not associated with maternal anemia. The results suggest that B cells and macrophages contribute to chronic PM in a process resembling lymphoid neogenesis. We propose a model where the production of Ig during chronic malaria may enhance inflammation by attracting and activating macrophages that, in turn, recruit B cells to further produce Ig in the intervillous spaces.