Position of lipidation influences anticancer activity of Smac analogs

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Micewicz, Ewa D.¹  Nguyen, Christine¹  Micewicz, Alina²  Waring, Alan J.³  McBrid, William H.¹  Ruchala, Piotr^4,5 

[1] Univ Calif Los Angeles, Dept Radiat Oncol, 10833 Le Conte Ave, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Volunteering Program, 10833 Le Conte Ave, Los Angeles, CA 90095 USA

[3] Harbor UCLA Med Ctr, Dept Med, Los Angeles Biomed Res Inst, 1000 West Carson St, Torrance, CA 90502 USA

[4] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, 760 Westwood Plaza, Los Angeles, CA 90024 USA

[5] Jane & Terry Semel Inst Neurosci & Human Behav, Pasarow Mass Spectrometry Lab, 760 Westwood Plaza, Los Angeles, CA 90024 USA

关键词: Smac mimetics;    Anticancer agents;    Lipid-conjugated peptides;    S-alkylation of peptides;    Apoptosis;    Inhibitor of menin-MLL1 protein interactions;   

DOI  :  10.1016/j.bmcl.2019.04.041

来源: Elsevier

【 摘 要 】

A small group of lipid-conjugated Smac mimetics was synthesized to probe the influence of the position of lipidation on overall anti-cancer activity. Specifically, new compounds were modified with lipid(s) in position 3 and C-terminus. Previously described position 2 lipidated analog M11 was also synthesized. The resulting mini library of Smacs lipidated in positions 2, 3 and C-terminus was screened extensively in vitro against a total number of 50 diverse cancer cell lines revealing that both the position of lipidation as well as the type of lipid, influence their anti-cancer activity and cancer type specificity. Moreover, when used in combination therapy with inhibitor of menin-MLL1 protein interactions, position 2 modified analog SM2 showed strong synergistic anti-cancer properties. The most promising lipid-conjugated analogs SM2 and SM6, showed favorable pharmacokinetics and in vivo activity while administered subcutaneously in the preclinical mouse model. Collectively, our findings suggest that lipid modification of Smacs may be a viable approach in the development of anti-cancer therapeutic leads.

【 授权许可】

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