Figure S1. Knockdown of NMT1 by shRNA-NMT1 inhibits Src myristoylation and proliferation of prostate cancer cells. Figure S2. Knockdown of Src and Fyn kinase inhibits the growth of prostate cancer cells. Figure S3. The contribution of myristoylation and palmitoylation to the activity of SFKs. Figure S4. Fyn kinase has no synergistic effect with androgen receptor (AR).
ARTICLE ABSTRACT
Protein N-myristoylation enables localization to membranes and helps maintain protein conformation and function. N-myristoyltransferases (NMT) catalyze co- or posttranslational myristoylation of Src family kinases and other oncogenic proteins, thereby regulating their function. In this study, we provide genetic and pharmacologic evidence that inhibiting the N-myristoyltransferase NMT1 suppresses cell-cycle progression, proliferation, and malignant growth of prostate cancer cells. Loss of myristoylation abolished the tumorigenic potential of Src and its synergy with androgen receptor in mediating tumor invasion. We identified the myristoyl-CoA analogue B13 as a small-molecule inhibitor of NMT1 enzymatic activity. B13 exposure blocked Src myristoylation and Src localization to the cytoplasmic membrane, attenuating Src-mediated oncogenic signaling. B13 exerted its anti-invasive and antitumor effects against prostate cancer cells, with minimal toxic side-effects in vivo. Structural optimization based on structure–activity relationships enabled the chemical synthesis of LCL204, with enhanced inhibitory potency against NMT1. Collectively, our results offer a preclinical proof of concept for the use of protein myristoylation inhibitors as a strategy to block prostate cancer progression. Cancer Res; 77(24); 6950–62. ©2017 AACR.
