Targeting N‐myristoyltransferase1 inhibits prostate cancer progression

Abstract

N‐myristoyltransferase (NMT) facilitates co/post‐translational myristoylation of several oncogenic proteins, regulating their functions in tumor progression. Overexpression of N‐myristoyltransferase (NMT), which has been shown to be upregulated in a variety of cancers, is associated with androgen independent prostate cancer cells. We demonstrate that genetically ablation of NMT1 inhibited proliferation of prostate cancer cells, tumor growth, and suppressed myristoylation profile of prostate cancer cells. Screening a panel of myristoyl‐CoA analogs against purified human NMT1 protein lead to identifying the B13/LCL4 as an inhibitor for NMT1. B13/LCL4 significantly supressed prostate cancer cell proliferation, migration, and invasion by cell cycle arrest, and inhibited the growth of prostate xenograft tumors with minimal pathological effect on major organs in vivo. Structure activity relationship based optimization of B13 led to LCL204, which showed better inhibitory properties twoards NMT1. We demonstrate that targeting protein myristoylation is a potential therapeutic approach to inhibit prostate tumor progression.Support or Funding InformationThis work was supported by NIH (R01CA172495) and DOD (W81XWH‐15‐1‐0507) to H. CaiThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.