Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8

Jiaang, Weir‐Torn; Chen, Yuan-Shou; Hsu, Tsu; Wu, Ssu-Hui; Chien, Chia‐Hui; Chang, Chung-Nien; Chang, Sheng-Ping; Lee, Shiow‐Ju; Chen, Xin

doi:10.1016/j.bmcl.2004.11.023

Cited by 91 publications

(33 citation statements)

References 20 publications

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“…5), a compound structurally unrelated to Val-boroPro that potently inhibits DPP8 and DPP9 (IC 50 values of 14 and 53 nM, respectively), but does not inhibit DPP4 or DPP7 (Supplementary Fig. 3a, Supplementary Table 1) 24,25 . Consistent with our hypothesis that DPP8 and DPP9 are the key targets, we observed that Val-boroPro and 1G244 induced similar LDH release from wild-type THP-1 cells and RAW 264.7 cells (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis

et al. 2016

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Val-boroPro (talabostat, PT-100), a nonselective inhibitor of post-proline cleaving serine proteases, stimulates mammalian immune systems through an unknown mechanism of action. Despite this lack of mechanistic understanding, Val-boroPro has attracted significant interest as a potential anticancer agent, reaching Phase III trials in humans. Here we show that Val-boroPro stimulates the immune system by triggering a proinflammatory form of cell death in monocytes and macrophages known as pyroptosis. We demonstrate that the inhibition of two serine proteases, DPP8 and DPP9, activates the proprotein form of caspase-1 independent of the inflammasome adaptor ASC. Activated pro-caspase-1 does not efficiently process itself or IL-1β, but does cleave and activate gasdermin D to induce pyroptosis. Mice lacking caspase-1 do not show immune stimulation after treatment with Val-boroPro. Our data identifies the first small molecule that induces pyroptosis and reveals a new checkpoint that controls the activation of the innate immune system.

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Section: Resultsmentioning

confidence: 99%

DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis

et al. 2016

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“…ARTICLE and synthesized by Jiaang et al 46 (Figure 3) This lead compound, already displaying some selectivity for DPP8, possesses the overall dipeptide-derived structure of all known DPP8/9 inhibitors, is the most active DPP8/9 inhibitor described to date and readily penetrates plasma membranes. 42 In addition, compared to the dimensions of several other reported DPP8/9 inhibitors, 7 is a large molecule that can be expected to probe a proportionally larger part of DPP8's and DPP9's active site, hence offering higher probability for detecting differences between both.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 97%

Structure–Activity Relationship Studies on Isoindoline Inhibitors of Dipeptidyl Peptidases 8 and 9 (DPP8, DPP9): Is DPP8-Selectivity an Attainable Goal?

et al. 2011

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This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIV's action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8-selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity.

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“…FAP inhibitors. DPP8 selective inhibitors containing an isoindoline at P 1 as in compound 20 were also described by Jiaang et al [89]. The cyclohexylglycine isoindoline 24 was more potent and selective for DPP8 than the corresponding pyrrolidine, piperidine and isoquinoline.…”

Section: Dipeptidyl Peptidase 8 (Dpp8) and Dipeptidyl Peptidase 9 (Dpmentioning

confidence: 96%

Prolyl Peptidases Related to Dipeptidyl Peptidase IV: Potential of Specific Inhibitors in Drug Discovery.

Veken

Haemers²,

Augustyns³

2007

CTMC

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Dipeptidyl peptidase IV (DPP IV) is a validated target for the treatment of type 2 diabetes, with several inhibitors currently in phase 3 clinical trials. This review will mainly focus on proline-specific dipeptidyl peptidases related to DPP IV: fibroblast activation protein (FAP), dipeptidyl peptidase 8 (DPP8), dipeptidyl peptidase 9 (DPP9) and dipeptidyl peptidase II (DPP II). The biochemical and biological properties of these enzymes will be discussed, as well as the therapeutic potential of their inhibition. The development of potent and selective inhibitors for each of these peptidases will be described.

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Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8

Cited by 91 publications

References 20 publications

DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis

DPP8 and DPP9 inhibition induces pro-caspase-1-dependent monocyte and macrophage pyroptosis

Structure–Activity Relationship Studies on Isoindoline Inhibitors of Dipeptidyl Peptidases 8 and 9 (DPP8, DPP9): Is DPP8-Selectivity an Attainable Goal?

Prolyl Peptidases Related to Dipeptidyl Peptidase IV: Potential of Specific Inhibitors in Drug Discovery.

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