First-in-Class Pan Caspase Inhibitor Developed for the Treatment of Liver Disease

Linton, Steven D.; Aja, Teresa; Armstrong, Robert A.; Bai, Xu; Chen, Long-Shiuh; Chen, Ning; Ching, Brett; Contreras, Patricia C.; Díaz, José-Luis; Fisher, Craig D.; Fritz, Lawrence C.; Gladstone, Patricia L.; Groessl, Todd; Gu, Xin; Herrmann, Julia; Hirakawa, Brad; Hoglen, Niel C.; Jahangiri, Kathy G.; Kalish, Vincent J.; Karanewsky, Donald S.; Kodandapani, Lalitha; Krebs, Joseph F.; McQuiston, Jeff; Meduna, Steven P.; Nalley, Kip; Robinson, Edward D.; Sayers, Robert O.; Sebring, Kristen; Spada, Alfred P.; Ternansky, Robert J.; Tomaselli, Kevin J.; Ullman, Brett R.; Valentino, Karen L.; Weeks, Suzanne; Winn, David T.; Wu, Joe C.; Yeo, Pauline; Zhang, Chengzhi

doi:10.1021/jm050307e

Cited by 94 publications

(49 citation statements)

References 26 publications

(37 reference statements)

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“…S2D), we next characterized the sensitivity of primary Spata2 −/− BMDMs and MEFs to necroptosis. We found that the treatment of mouse TNFα plus IDN-6556, a pan-caspase inhibitor that has been tested in human clinical trials (Linton et al 2005), was sufficient to induce the death of primary wild-type BMDMs, whereas Spata2 −/− BMDMs were highly resistant (Fig. 1A,B).…”

Section: Spata2mentioning

confidence: 94%

SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination

Wei

Liu

et al. 2017

Genes Dev.

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Stimulation of cells with TNFα leads to the formation of the TNF-R1 signaling complex (TNF-RSC) to mediate downstream cellular fate decision. Activation of the TNF-RSC is modulated by different types of ubiquitination and may lead to cell death, including apoptosis and necroptosis, in both RIPK1-dependent and RIPK1-independent manners. Spata2 (spermatogenesis-associated 2) is an adaptor protein recruited into the TNF-RSC to modulate the interaction between the linear ubiquitin chain assembly complex (LUBAC) and the deubiquitinase CYLD (cylindromatosis). However, the mechanism by which Spata2 regulates the activation of RIPK1 is unclear. Here, we report that Spata2-deficient cells show resistance to RIPK1-dependent apoptosis and necroptosis and are also partially protected against RIPK1-independent apoptosis. Spata2 deficiency promotes M1 ubiquitination of RIPK1 to inhibit RIPK1 kinase activity. Furthermore, we provide biochemical evidence for the USP domain of CYLD and the PUB domain of the SPATA2 complex preferentially deubiquitinating the M1 ubiquitin chain in vitro. Spata2 deficiency also promotes the activation of MKK4 and JNK and cytokine production independently of RIPK1 kinase activity. Spata2 deficiency sensitizes mice to systemic inflammatory response syndrome (SIRS) induced by TNFα, which can be suppressed by RIPK1 inhibitor Nec-1s. Thus, Spata2 can regulate inflammatory response and cell death in both RIPK1-dependent and RIPK1-independent manners.

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Section: Spata2mentioning

confidence: 94%

SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination

Wei

Liu

et al. 2017

Genes Dev.

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“…Putative drug targets derived from cell death studies have permitted the advancement through different clinical phases of pharmacological candidates. 23 In fact, most of the key players in the apoptotic signaling pathway have been explored as drug targets: death receptors that control apoptosis induction from the cell surface, 178 caspases that are the executioners of apoptosis, 26,27 endogenous caspase inhibitors as IAP, 179 and Bcl-2 protein family members. 120 However, the apoptosome and its primary scaffolding protein Apaf-1, have been less tractable as drug targets.…”

Section: Discussionmentioning

confidence: 99%

Molecules that modulate Apaf‐1 activity

Pérez‐Payá

Orzáez

Mondragón

et al. 2011

Medicinal Research Reviews

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Programmed cell death, apoptosis, is a highly regulated cellular pathway, responsible for the elimination of cells in the organism that are no longer needed or extensively damaged. Defects in the regulation of apoptosis could be at the molecular basis of different diseases, either when it is insufficient or excessive. The formation of the macromolecular complex, apoptosome, is a key event in this pathway, which has also been defined as the intrinsic apoptosis pathway. The apoptosome is a holoenzyme multiprotein complex formed by cytochrome c-activated apoptotic protease-activating factor (Apaf-1), dATP, and procaspase-9. Recent studies have produced a wealth of information about the regulation and functions of Apaf-1, but additional studies aimed at elucidating its role as a signaling device at the crosstalk between different signaling pathways are needed to take advantage for the development of modulators of apoptosis pathways and possible therapeutic applications.

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“…We then decided to use as starting material the dipeptidyl aldehydes 4aed synthesized from the correspondent dipeptide acids [11] using Weinreb chemistry [10]. Deprotection of vinyl sulfones 5aeh with TFA, afforded vinyl sulfones 6aeh with yields of 34e75% from the correspondent aldehydes (Scheme 1).…”

Section: Chemistrymentioning

confidence: 99%