Abstract
Abstract
N-myristoyltransferase (NMT) facilitates co/post-translational myristoylation of several oncogenic proteins, regulating their functions in tumor progression. N-myristoyltransferase (NMT), which has been shown to be upregulated in a variety of cancers, is overexpressed in 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 leads to identifying the B13 as an inhibitor for NMT1. B13 significantly suppressed prostate cancer cell proliferation, migration, and invasion by cell cycle arrest, and inhibited the growth of prostate xenograft tumors with minimal pathologic effect on major organs in vivo. Structure activity relationship based optimization of B13 led to LCL204, which showed better inhibitory properties towards NMT1. We demonstrate that targeting protein myristoylation is a potential therapeutic approach to inhibit prostate tumor progression.
Citation Format: Omar Alsaidan, Sungjin Kim, Octavia Goodwin, Qianjin Li, Aiping Bai, Alicja Bielawska, George Zheng, Iryna Lebedyeva, Thomas Albers, James S. Norris, Scott D. Pegan, Houjian Cai. Targeting N-myristoyltransferase 1 inhibits prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A070.