October 29, 2020: Percentage of maximum growth inhibition of various cell lines following 72 h treatment with 1 μM of PCLX-001 using the Oncolines™ cell line screen. Corresponding violin graphs compare the average PCLX-001-mediated growth inhibition on hematological cancer cell lines to cancer cell lines of other origins combined as calculated from the cell screen (Unpaired t test, two-tailed P < 0.0001). Quartiles are separated by dotted lines. Error bars represent standard deviation within each group (Beauchamp et al., 2020).
The power of cancer cell panel profiling for proof-of-concept studies in Nat. Commun.
Oss, October 28, 2020 – The paper “Targeting N-myristoylation for therapy of B-cell lymphomas” in Nature Communications by Beauchamp et al. describes the value of cancer cell line panel profiling for in vitro proof-of-concept studies for the novel pan-NMT inhibitor PCLX-001. We are proud that the paper refers to Oncolines™ profiling of PCLX-001.
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.
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