At least six cellular pathways leading to activation of NFκB-family transcription factors have been identified, participating in host-defense, immunity, inflammation, and cancer. The pathway initiated by Protein Kinase C (PKC) family kinase is critical for signaling downstream of antigen receptors in T-cells and B-cells, as well as many growth factor receptors and some GPCRs that stimulate intracellular Ca2+ elevations. This pathway often involves a multi-component protein complex that includes CARMA, Bcl-10, and MALT1. Previously, a potent (~67 nM) and selective probe (ML029, Pubchem CID2858522) was identified as an inhibitor of the PKC-initiated NF-κB pathway after a battery of 12 secondary and counter-screen assays. However, this probe appeared potent only in the original HEK293 reporter cell line and some types of primary lymphocytes, with little potency in several other tumor cell lines. We used HTS assays employing NF-κB reporter genes in T-cell and B-cell lines for screening the ~330,600 compound MLSMR collection to identify novel pathway-selective inhibitors. We now disclose the discovery and characterization of two novel potent small molecule cell-active NF-κB inhibitors that are both (a) selective for the NF-κB pathway induced by PKC activators (phorbol myristic acetate/ionomycin) and (b) selective for B-cells. The first oxadiazole-based probe (ML236, PubChem CID665654) is potent (35 nM) in a B-cell line and >400-fold selective over both the NF-κB activation in T-cells and against TNFα-mediated NF-κB activation. In comparison, the second oxazole-based probe (ML237, PubChem CID4174238) is also potent (208 nM) in a B-cell line and >400 fold selective over both the NF-κB activation in T-cells and against TNFα-mediated NF-κB activation. The synthetic methodology, SAR development, and initial pharmacologic characterization are also presented. These probe molecules will be used to define the B-cell specific targets along these pathways and will serve as tools to reveal hitherto unknown components of these signaling pathways. These probes will prove useful to researchers working in immunology, autoimmune diseases, transplantation and allograft rejection, lymphoid malignancies, immune signaling, and general signal transduction.