{'fraction_non_alphanumeric': 0.023790642347343377, 'fraction_numerical': 0.007137192704203013, 'mean_word_length': 6.294797687861272, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Development of Substrate‐Derived Sirtuin Inhibitors with Potential Anticancer Activity

RhoGDIα is a key regulator of Rho proteins, coordinating their GTP/GDP and membrane/cytosol cycle. Recently, it was demonstrated by quantitative mass spectrometry that RhoGDIα is heavily targeted by post‐translational lysine acetylation. For one site in its N‐terminal domain, namely K52, we reported earlier that acetylation completely switches off RhoGDIα function. Herein we show that K52‐acetylated RhoGDIα is specifically deacetylated by the sirtuin deacetylase Sirt2. We show that acetylation at K52 decelerates cervical cancer cell proliferation, suggesting RhoGDIα acetylation to be a promising therapeutic target. We demonstrate that treatment of cervical cancer cells with a RhoGDIα‐derived K52‐trifluoroacetylated, substrate‐derived peptidic sirtuin inhibitor severely impairs cell proliferation. Finally, we conclude that the potency of substrate‐derived sirtuin inhibitors depends on structural features, the substrate‐derived amino acid sequence as a determinant for selectivity, as well as the presence of an acetyl‐lysine analogue to increase its potency. These data reveal a prospective therapeutic potential for novel substrate‐derived sirtuin inhibitors.