ddd-85646 and Lymphoma--B-Cell

Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma.

Topics: Acyltransferases; Adenine; Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dasatinib; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Female; Humans; Lymphoma, B-Cell; Mice; Mice, SCID; Models, Biological; Myristic Acid; Piperidines; Pyrazoles; Pyrimidines; Receptors, Antigen, B-Cell; Signal Transduction; src-Family Kinases; Sulfonamides; Xenograft Model Antitumor Assays