Structure-activity relationships of piperazine-2-one derivatives as novel human ClpP activators

The human caseinolytic protease P (hClpP) is a serine protease localized at the mitochondrial matrix. It is involved in maintaining the homeostasis of the mitochondrial proteome. hClpP, together with the AAA+ unfoldase protein (ClpX), forms the complex hClpXP, which primary function is to facilitate the turnover of degraded proteins to prevent their accumulation, causing disruption of normal cellular function. Although, the pathological role of hClpP in cancer is not yet fully understood, its expression is upregulated in several types of solid tumors, such as lung, stomach, liver, thyroid, bladder, breast, ovary, prostate, testis, and brain. Therefore, chemical modulators of hClpP proteolytic activity might have potential antitumor use. hClpP activators act by disrupting the hClpXP complex, generating a physical detachment of ClpX from ClpP still maintaining ClpP in its active state. Several hClpP activators are known: imipridones, macrocyclic acyldepsipeptides (ADEPs), and oxadiazonocarboxyamides. The most successful ClpP activators belong to the imipridone class and its protype is ONC201, then through in silico techniques a new scaffold tetrahydropyridopyrimidinone (THPPD) was identified, and more potent activators of hClpP were obtained (eg TR57). Such a scaffold was further simplified to 1,4-dibenzylpiperazine-2-one derivatives (DA series) and preliminary information obtained from a structure-activity relationship study aimed at identifying the best isosteric chemical structure modifications to produce potent hClpP activators (nM scale) will be presented.