<jats:title>Abstract</jats:title><jats:p>Three new 3‐amino‐6‐hydroxy‐2‐piperidone (Ahp)‐containing cyclic depsipeptides, named loggerpeptins A–C (<jats:bold>1</jats:bold><jats:italic>–</jats:italic><jats:bold>3</jats:bold>), along with molassamide (<jats:bold>4</jats:bold>), were discovered from a marine cyanobacterium, extending the structural diversity of this prevalent scaffold of cyanobacterial serine protease inhibitors. Molassamide, which contains a 2‐amino‐butenoic (Abu) unit in the cyclic core, was the most potent and selective analogue against human neutrophil elastase (HNE). Given the growing evidence supporting the role of HNE in breast cancer progression and metastasis, we assessed the cellular effects of compounds <jats:bold>3</jats:bold> and <jats:bold>4</jats:bold> in the context of targeting invasive breast cancer. Both compounds inhibited cleavage of the elastase substrate CD40 in biochemical assays; however, only <jats:bold>4</jats:bold> exhibited significant cellular activity. As CD40 and other receptor proteolytic processing culminates in NFκB activation, we assessed the effects of <jats:bold>4</jats:bold> on the expression of target genes, including <jats:italic>ICAM‐1</jats:italic>. ICAM‐1 is also a direct target of elastase and, in our studies, compound <jats:bold>4</jats:bold> attenuated both elastase‐induced <jats:italic>ICAM‐1</jats:italic> gene expression and ICAM‐1 proteolytic processing by elastase, revealing a potential dual effect on migration through modulation of gene expression and proteolytic processing. Molassamide also specifically inhibited the elastase‐mediated migration of highly invasive triple<jats:italic>‐</jats:italic>negative breast cancer cells.