Structure–activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors

Teng, Xin; Keys, Heather R.; Jeevanandam, Arumugasamy; Porco, John A.; Degterev, Alexei; Yuan, Junying; Cuny, Gregory D.

doi:10.1016/j.bmcl.2007.10.024

Cited by 44 publications

(20 citation statements)

References 31 publications

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“…On the other hand, extensive structure-activity relationship (SAR) analysis of Nec-1 and other necrostatins revealed that even small changes to these molecules led to the robust loss of activity and failed to identify clear directions to significantly increase affinity of these moderately potent (e.g. cellular IC 50 of 7Cl-O-Nec-1=210 nM) molecules (Choi et al, 2012; Jagtap et al, 2007; Teng et al, 2005; Teng et al, 2007; Teng et al, 2008). Furthermore, necrostatins could have physical limitations on maximal robustness due to the small size of the molecules and an energy penalty due to the loss of a strong Glu/Lys interaction in αC-Glu-out conformation (Fig.…”

Section: Introductionmentioning

confidence: 99%

Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

et al. 2015

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Summary RIPK1 and RIPK3, two closely related RIPK family members, have emerged as important regulators of pathologic cell death and inflammation. In the current work, we report that the Bcr-Abl inhibitor and anti-leukemia agent ponatinib is also a first-in-class dual inhibitor of RIPK1 and RIPK3. Ponatinib potently inhibited multiple paradigms of RIPK1- and RIPK3-dependent cell death and inflammatory TNFα gene transcription. We further describe design strategies that utilize the ponatinib scaffold to develop two classes of inhibitors (CS and PN series), each with greatly improved selectivity for RIPK1. In particular, we detail the development of PN10, a highly potent and selective ‘hybrid’ RIPK1 inhibitor, capturing the best properties of two different allosteric RIPK1 inhibitors, ponatinib and necrostatin-1. Finally, we show that RIPK1 inhibitors from both classes are powerful blockers of TNF-induced injury in vivo. Altogether, these findings outline promising candidate molecules and design approaches for targeting RIPK1/3-driven inflammatory pathologies.

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Section: Introductionmentioning

confidence: 99%

Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

et al. 2015

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“…Indeed, a systematic transplantation study demonstrated that the teratoma-forming propensity of various mouse iPSC-derived neurospheres correlated with the persistence of residual undifferentiated cells (9). Because hESCs and hiPSCs also exhibit marked variations in differentiation efficiencies (and remaining undifferentiated cells) (10)(11)(12)(13), it is critical to remove all residual hiPSCs with teratoma potential before their clinical application. Despite numerous attempts at blocking teratoma formation, including introduction of suicide genes (14) or selecting the desired cell type (15), immunodepletion (16), or introducing cytotoxic antibody (17), a clinically viable strategy to eliminate teratoma formation remains to be developed (8,18).…”

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confidence: 99%

Inhibition of pluripotent stem cell-derived teratoma formation by small molecules

Lee

Moon

Jeong

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

221

198

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The future of safe cell-based therapy rests on overcoming teratoma/ tumor formation, in particular when using human pluripotent stem cells (hPSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Because the presence of a few remaining undifferentiated hPSCs can cause undesirable teratomas after transplantation, complete removal of these cells with no/minimal damage to differentiated cells is a prerequisite for clinical application of hPSC-based therapy. Having identified a unique hESC signature of pro-and antiapoptotic gene expression profile, we hypothesized that targeting hPSC-specific antiapoptotic factor(s) (i.e., survivin or Bcl10) represents an efficient strategy to selectively eliminate pluripotent cells with teratoma potential. Here we report the successful identification of small molecules that can effectively inhibit these antiapoptotic factors, leading to selective and efficient removal of pluripotent stem cells through apoptotic cell death. In particular, a single treatment of hESC-derived mixed population with chemical inhibitors of survivin (e.g., quercetin or YM155) induced selective and complete cell death of undifferentiated hPSCs. In contrast, differentiated cell types (e.g., dopamine neurons and smooth-muscle cells) derived from hPSCs survived well and maintained their functionality. We found that quercetin-induced selective cell death is caused by mitochondrial accumulation of p53 and is sufficient to prevent teratoma formation after transplantation of hESC-or hiPSC-derived cells. Taken together, these results provide the "proof of concept" that small-molecule targeting of hPSC-specific antiapoptotic pathway(s) is a viable strategy to prevent tumor formation by selectively eliminating remaining undifferentiated pluripotent cells for safe hPSC-based therapy.

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“…Recently, a series of (1,2,3)thiadiazole benzylamides were shown to be potent necroptosis inhibitors (called necrostatins) [131]. Previous reports indicated that necrostatins function as necroptosis inhibitors in FADDdeficient human Jurkat T cells following treatment with TNF- [132].…”

Section: Necroptosismentioning

confidence: 98%

Cell Death by Necrosis, a Regulated Way to Go

Henríquez

Armisén²,

Stutzin³

et al. 2008

CMM

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Apoptosis is a programmed form of cell death with well-defined morphological traits that are often associated with activation of caspases. More recently evidence has become available demonstrating that upon caspase inhibition alternative programs of cell death are executed, including ones with features characteristic of necrosis. These findings have changed our view of necrosis as a passive and essentially accidental form of cell death to that of an active, regulated and controllable process. Also necrosis has now been observed in parallel with, rather than as an alternative pathway to, apoptosis. Thus, cell death responses are extremely flexible despite being programmed. In this review, some of the hallmarks of different programmed cell death modes have been highlighted before focusing the discussion on necrosis. Obligatory events associated with this form of cell death include uncompensated cell swelling and related changes at the plasma membrane. In this context, representatives of the transient receptor channel family and their regulation are discussed. Also mechanisms that lead to execution of the necrotic cell death program are highlighted. Emphasis is laid on summarizing our understanding of events that permit switching between cell death modes and how they connect to necrosis. Finally, potential implications for the treatment of some disease states are mentioned.

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Structure–activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors

Cited by 44 publications

References 31 publications

Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

Structure Guided Design of Potent and Selective Ponatinib-Based Hybrid Inhibitors for RIPK1

Inhibition of pluripotent stem cell-derived teratoma formation by small molecules

Cell Death by Necrosis, a Regulated Way to Go

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