2023
DOI: 10.1016/j.str.2022.12.002
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Potent ClpP agonists with anticancer properties bind with improved structural complementarity and alter the mitochondrial N-terminome

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Cited by 19 publications
(23 citation statements)
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“…Another evolving approach to targeting mitochondrial transcription includes the recently discovered small molecule activators of the mitochondrial protease ClpP (herein referred to as ClpP agonists). These compounds include the imipridones ONC201 and ONC206 (currently in clinical trials), the more potent TR compounds, and other recently discovered molecules [ 33 , 34 , 35 , 36 , 37 ]. Studies from our laboratory and others show that ClpP agonists rapidly deplete POLRMT protein and other key proteins involved in mtDNA transcription [ 33 , 34 , 35 , 38 ].…”
Section: Mitochondrial Transcription and Metabolism As Targets For Ne...mentioning
confidence: 99%
“…Another evolving approach to targeting mitochondrial transcription includes the recently discovered small molecule activators of the mitochondrial protease ClpP (herein referred to as ClpP agonists). These compounds include the imipridones ONC201 and ONC206 (currently in clinical trials), the more potent TR compounds, and other recently discovered molecules [ 33 , 34 , 35 , 36 , 37 ]. Studies from our laboratory and others show that ClpP agonists rapidly deplete POLRMT protein and other key proteins involved in mtDNA transcription [ 33 , 34 , 35 , 38 ].…”
Section: Mitochondrial Transcription and Metabolism As Targets For Ne...mentioning
confidence: 99%
“…Similar to ADEPs, imipridones directly binds to ClpP, and displace ClpX, and the bindings triggers the opening of channel-like pore of ClpP, and thereby increase its protease activity without the ClpX [ 233 , 271 , 293 ] ( Figure 6 B). Recently, X-ray crystallography demonstrated that TR compounds bind to ClpP, with enhanced binding affinities due to their greater shape and charge complementarity with the surface hydrophobic pockets of ClpP [ 294 ] ( Figure 7 C). Moreover, N-terminome profiling of MDA-MB-231 cell line upon treatment with one of TR compounds revealed the global proteomic changes and characterized the sequence and structural properties for protein cleavage generated upon TR compound-induced ClpP-dependent proteolysis of cellular proteins [ 294 ].…”
Section: Clppmentioning
confidence: 99%
“…Compared with imipridones, TR compounds show significantly higher potency; IC 50 of TR-57 and TR-107 exert anti-proliferative effects in the 10–25 nanomolar in TNBC cells ( Table 2 ). The superior potency of TR compounds over other ClpP agonists is attributed to the better binding properties to ClpP [ 294 ].…”
Section: Preclinical Studies Using Clpp Agonists In Breast Cancersmentioning
confidence: 99%
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“…Typically, ClpP activators have similar structural characteristics. They usually consist of a hydrophobic group at both ends and a supportive scaffold in the middle, forming a “clamp” that binds to the ClpP groove. , For example, the substituted phenyl groups at both ends of CCG1423 are embedded in the hydrophobic cavity as clamp A and clamp B, respectively (Figure F). Dependent on the intermediate α-aminooxypropionic acid, the compound constitutes a structure spatially complementary to the surface of the ClpP groove (Figure E,F).…”
Section: Introductionmentioning
confidence: 99%