Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors

Ganellin, C. Robin; Bishop, Paul; Bambal, Ramesh; Chan, S. M. T.; Leblond, Bertrand; Moore, Andrew N. J.; Zhao, Lihua; Bourgeat, Pierre; Rose, Christiane; Vargas, Froylan; Schwartz, Jean‐Charles

doi:10.1021/jm0500830

Cited by 7 publications

(2 citation statements)

References 32 publications

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“…Butabindide is a TPPII specific reversible and competitive inhibitor but has low membrane permeability [26][27][28]. Moreover it is instable in aqueous solutions and even small amounts of fetal calf serum in culture media prevent the inhibitory effect of butabindide in vitro, thus, its action can be observed only in serum-free systems [26,29].…”

Section: Discussionmentioning

confidence: 99%

Semispecific TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) displays cytotoxic activity by induction of apoptosis, autophagy and protein aggregation in U937 cells

Biały

Fayet

Wilczyński

et al. 2019

Folia Histochem Cytobiol.

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Introduction. The main component of extralysosomal proteolysis is the ubiquitin-proteasome system (UPS), which is supplemented by tripeptidyl peptidase II (TPPII). That system is a target for anticancer strategies by using proteasome inhibitors. Data from several studies on leukemic cells share evidence for the beneficial and potential role of TPPII in cell survivability. Therefore, the aim of this work was to analyze the effect of AAF-cmk, a membrane permeable semi-specific TPPII inhibitor, on human monocytic leukemic cells U937 for translational research. Material and methods. We studied the viability of U937 cells incubated with AAF-cmk using tetrazolium salt reduction assay (MTT) and apoptosis induction by assessing caspase activation by Western blotting and Annexin V binding assays. Transmission electron microscopy (TEM), a gold standard for apoptosis and autophagy detection, was used to assess the ultrastructure of U937 cells. Results. Incubation of cells with AAF-cmk reduced their viability and induced apoptosis by intrinsic pathway. In groups treated with AAF-cmk, activation of caspases 9 and 3 was observed and caspase inhibition by zVDA restored cell viability. TEM revealed the presence of ultrastructural features of apoptosis and authophagy. Moreover, we identified two types of protein aggregates. The first one was found in close proximity to the endoplasmic reticulum (ER) and corresponds to Aggresome-Like Structure (ALIS); however, the second novel type of aggregate was not related to ER elements, but rather to free cytosolic ribosomes. This type did not correspond to the aggresome neither in localization nor the structure, thus we referred these aggregates as ALiSNER (Aggresome-Like Structure Not Associated With the ER). Conclusions. Our results provide novel and important findings about the role of TPPII in protein homeostasis and cell survival. Since semispecific TPPII inhibitor AAF-cmk displays cytotoxic activity against leukemic U937 cells in vitro it can be considered as a potential anticancer agent.

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Section: Discussionmentioning

confidence: 99%

Semispecific TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) displays cytotoxic activity by induction of apoptosis, autophagy and protein aggregation in U937 cells

Biały

Fayet

Wilczyński

et al. 2019

Folia Histochem Cytobiol.

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“…Synthesis of the cis proline derivative 36 , shown in Scheme , started from commercially available (2 S ,4 R )-1-( tert -butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid ( 54 ) and in three steps was elaborated to give 55 . Oxidation of the alcohol followed by a Wittig reaction and reduction provided 36 …”

Section: Chemistrymentioning

confidence: 99%

Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists

et al. 2012

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A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.

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Design of Serine Protease Inhibitors

Ghosh¹,

Gemma²

2014

Structure‐Based Design of Drugs and Other Bioactive Molecules

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Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors

Cited by 7 publications

References 32 publications

Semispecific TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) displays cytotoxic activity by induction of apoptosis, autophagy and protein aggregation in U937 cells

Semispecific TPPII inhibitor Ala-Ala-Phe-chloromethylketone (AAF-cmk) displays cytotoxic activity by induction of apoptosis, autophagy and protein aggregation in U937 cells

Discovery of a Novel Class of Potent and Orally Bioavailable Sphingosine 1-Phosphate Receptor 1 Antagonists

Design of Serine Protease Inhibitors

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