Development of 2-Thioxoquinazoline-4-one Derivatives as Dual and Selective Inhibitors of Dynamin-Related Protein 1 (Drp1) and Puromycin-Sensitive Aminopeptidase (PSA)

Numadate, Akiyoshi; Mita, Yusuke; Matsumoto, Yotaro; Fujii, Shinya; Hashimoto, Yuichi

doi:10.1248/cpb.c14-00333

Cited by 19 publications

(21 citation statements)

References 22 publications

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“…One of the major observations reported by Bordt et al () is that mdivi‐1 inhibits the GTPase activity of yeast but not mammalian Drp1. However, Numadate et al () reported finding inhibition of mammalian Drp1 GTPase activity by mdivi‐1 with a Ki of 13 μM, similar to that determined by Cassidy‐Stone et al () for yeast Drp1. I note that Numadate et al () report obtaining the open reading frame cDNA for Drp1 from GeneCopoeia™ (http://www.genecopoeia.com) that only has human and mouse Drp1 in its catalog, but we were not able to obtain a response from the authors to verify the species (that is not reported).…”

Section: Introductionsupporting

confidence: 68%

“…However, Numadate et al () reported finding inhibition of mammalian Drp1 GTPase activity by mdivi‐1 with a Ki of 13 μM, similar to that determined by Cassidy‐Stone et al () for yeast Drp1. I note that Numadate et al () report obtaining the open reading frame cDNA for Drp1 from GeneCopoeia™ (http://www.genecopoeia.com) that only has human and mouse Drp1 in its catalog, but we were not able to obtain a response from the authors to verify the species (that is not reported). However, direct communication with a GeneCopoeia representative verified they do not carry the yeast Drp1 ORF cDNA.…”

Section: Introductionsupporting

confidence: 68%

“…Whether Numadate used human or mouse Drp1 remains unclear. Regardless, while there is a growing consensus that mdivi-1 inhibits yeast Drp1 GTPase activity, the studies by Bordt et al (2017) and Numadate et al (2014) present opposing findings for the effects of mdivi-1 on mammalian GTPase activity. Clearly, additional investigation of the effects of mdivi-1 on mammalian Drp1 GTPase activity and oligomerization into rings is required to resolve the discrepancy.…”

Section: Biochemical Analysis Of Mdivi-1 As An Inhibitor Of Drp1 Gtpamentioning

confidence: 99%

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To mdivi‐1 or not to mdivi‐1: Is that the question?

Smith

Gallo

2017

Developmental Neurobiology

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The fission/division and fusion of mitochondria are fundamental aspects of mitochondrial biology. The balance of fission and fusion sets the length of mitochondria in cells to serve their physiological requirements. The fission of mitochondria is markedly induced in many disease states and in response to cellular injury, resulting in the fragmentation of mitochondria into dysfunctional units. The mechanism that drives fission is dependent on the dynamin related protein 1 (Drp1) GTPase. mdivi-1 is a quinazolinone originally described as a selective inhibitor of Drp1, over other dynamin family members, and reported to inhibit mitochondrial fission. A recent study has challenged the activity of mdivi-1 as an inhibitor of Drp1. This study raises serious issues regarding the interpretation of data addressing the effects of mdivi-1 as reflective of the inhibition of Drp1 and thus fission. This commentary considers the evidence for and against mdivi-1 as an inhibitor of Drp1 and presents the following considerations; (1) the activity of mdivi-1 toward Drp1 GTPase activity requires further biochemical investigation, (2) as there is a large body of literature using mdivi-1 in vitro with effects as predicted for inhibition of Drp1 and mitochondrial fission, reviewed herein, the evidence is in favor of mdivi-1’s originally described bioactivity, and (3) until the issue is resolved, experimental interpretations for the effects of mdivi-1 on inhibition of fission in cell and tissue experiments warrants stringent positive controls directly addressing the effects of mdivi-1 on fission.

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Section: Introductionsupporting

confidence: 68%

Section: Introductionsupporting

confidence: 68%

Section: Biochemical Analysis Of Mdivi-1 As An Inhibitor Of Drp1 Gtpamentioning

confidence: 99%

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To mdivi‐1 or not to mdivi‐1: Is that the question?

Smith

Gallo

2017

Developmental Neurobiology

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“…Initially discovered by Nunnari and colleagues, mdivi-1 was shown to be specific and potent inhibitor of GTPase activity of yeast Dnm1, a homolog of mammalian Drp1 22 . Subsequently, this small molecule was also demonstrated to block Drp1 GTPase activity in human recombinant Drp1 68 and in mammalian neuronal cells 28 . GTPase activity of Drp1 is required for Drp1 oligomerization.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease

Bido

Soria

Fan

et al. 2017

Sci Rep

102

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Alpha-synuclein (α-syn) is involved in both familial and sporadic Parkinson’s disease (PD). One of the proposed pathogenic mechanisms of α-syn mutations is mitochondrial dysfunction. However, it is not entirely clear the impact of impaired mitochondrial dynamics induced by α-syn on neurodegeneration and whether targeting this pathway has therapeutic potential. In this study we evaluated whether inhibition of mitochondrial fission is neuroprotective against α-syn overexpression in vivo. To accomplish this goal, we overexpressed human A53T-α- synuclein (hA53T-α-syn) in the rat nigrostriatal pathway, with or without treatment using the small molecule Mitochondrial Division Inhibitor-1 (mdivi-1), a putative inhibitor of the mitochondrial fission Dynamin-Related Protein-1 (Drp1). We show here that mdivi-1 reduced neurodegeneration, α-syn aggregates and normalized motor function. Mechanistically, mdivi-1 reduced mitochondrial fragmentation, mitochondrial dysfunction and oxidative stress. These in vivo results support the negative role of mutant α-syn in mitochondrial function and indicate that mdivi-1 has a high therapeutic potential for PD.

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“…Indeed, the current assumption that mitodynamics drugs such as mdivi-1 can cause a loss of the functional properties possessed by CSCs should be reconsidered in light of the recently reported finding that mdivi-1 is a poor inhibitor of recombinant Drp1 GTPase activity, but modifies mitochondrial ROS production via reversible inhibition of mitochondrial complex I without affecting mitochondrial elongation [77]. New pharmacological strategies are being developed in our laboratory to design negative allosteric modulators of Drp1 activity based on the key structural features recently described in more potent and specific mdivi-1 derivatives [78]. Such deconstruction of Drp1 druggability aims also to generate new Drp1-targeted small molecules capable of mimicking the chemical behavior of the so-called P110 peptide, which has been shown to selectively prevent the GTPase activity of Drp1 and recruitment to mitochondria via blocking the interaction between Drp1 and one of its receptors (Fis1) at the mitochondrial outer membrane only under pathological conditions [79].…”

Section: Mitostemness-targeting Drugs As Anti-csc Therapies: the Chalmentioning

confidence: 99%

Mitostemness

et al. 2018

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Unraveling the key mechanisms governing the retention versus loss of the cancer stem cell (CSC) state would open new therapeutic avenues to eradicate cancer. Mitochondria are increasingly recognized key drivers in the origin and development of CSC functional traits. We here propose the new term "mitostemness" to designate the mitochondria-dependent signaling functions that, evolutionary rooted in the bacterial origin of mitochondria, regulate the maintenance of CSC self-renewal and resistance to differentiation. Mitostemness traits, namely mitonuclear communication, mitoproteome components, and mitochondrial fission/fusion dynamics, can be therapeutically exploited to target the CSC state. We briefly review the pre-clinical evidence of action of investigational compounds on mitostemness traits and discuss ongoing strategies to accelerate the clinical translation of new mitostemness drugs. The recognition that the bacterial origin of present-day mitochondria can drive decision-making signaling phenomena may open up a new therapeutic dimension against life-threatening CSCs. New therapeutics aimed to target mitochondria not only as biochemical but also as biophysical and morpho-physiological hallmarks of CSC might certainly guide improvements to cancer treatment.

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Development of 2-Thioxoquinazoline-4-one Derivatives as Dual and Selective Inhibitors of Dynamin-Related Protein 1 (Drp1) and Puromycin-Sensitive Aminopeptidase (PSA)

Cited by 19 publications

References 22 publications

To mdivi‐1 or not to mdivi‐1: Is that the question?

To mdivi‐1 or not to mdivi‐1: Is that the question?

Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease

Mitostemness

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