Structural simplification of imipridones to speed up the knowledge on the nature of the interactions with the human ClpP, a mitochondrial protease strictly linked to DIPG

The human ClpP (hClpP), a mitochondrial matrix caseinolytic protease, is responsible for the mitochondria proteostasis by degradation of misfolded and damaged proteins under the physiological regulation of the AAA+ ATPase chaperone ClpX. By consuming ATP, ClpX recognizes, unfolds, and translocates the tagged proteins into the hClpP tetradecamer proteolytic cylindrical chamber to be degraded. High hClpP expression levels were found in multiple tumor tissues in which may play an oncogenic role. Given that hClpP inhibition by small molecule inhibitors has shown therapeutic effects in several tumour types, the chemo-activation of mitochondrial hClpP can also exhibits promising anticancer properties1. The most successful ClpP activators belong to the class of imipridones and ONC201, also named dordaviprone, is the first-in-class of the series (Figure 1). Currently ONC201 is worldwide evaluated in a Phase 3 study in H3K27-altered glioma, including Diffuse Intrinsic Pontine Glioma (DIPG)2. Through a rational drug design approach, the tetrahydropyridopyrimidinone (THPPD) was identified as a new scaffold for hClpP potent activators development (e.g. TR57). Structure optimization led to a novel series of piperazine derivatives as putative hClpP activators. A structure-activity relationship study aimed at deeply knowing the nature of the interactions with the hClpP to identify a better hClpP activator will be presented.