P1/2, N=21, Terminated, Ascentage Pharma Group Inc. | N=44 --> 21 | Recruiting --> Terminated; Company Strategy

P1/2, N=40, Terminated, Ascentage Pharma Group Inc. | N=104 --> 40 | Recruiting --> Terminated; Company Strategy

As small-molecule second mitochondria-derived activator of caspases (SMAC) mimetics have been shown to increase OV-mediated death in cancer models, we used the SMAC mimetics LCL-161 and birinapant alongside MG1 to enhance the killing of HIV-infected cell lines and monocyte-derived macrophages (MDMs). This cell death occurs via both caspase-dependent and caspase-independent mechanisms and is not completely dependent on tumor necrosis factor alpha (TNFα). Together, these results show that the use of SMAC mimetics alongside OVs may be a viable strategy to eradicate latently/persistently HIV-infected cells.

In vitro, corilagin inhibits necroptosis induced by either tuberculosis, tumor necrosis factor-α (TNF-α), LCL-161, and inhibitor (IDN-6556) (TSI) (tumor necrosis TNF-α combined with LCL-161 (a Smac mimic) and pan-caspase inhibitor IDN-6556), or lipopolysaccharide (LPS) with IDN-6556. In a mouse model of sepsis associated with necroptosis, corilagin administration reduces the severity of LPS-induced acute lung injury, correlating with decreased MLKL phosphorylation in lung tissues. These results indicate that corilagin attenuates RIPK1/RIPK3/MLKL signaling, potentially through reducing mtROS production, thereby inhibiting necroptosis and offering protection against LPS-induced acute lung injury.

In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.

Furthermore, more nuclear chromatin condensation and cell shrinkage were observed in the GDC-0152 treatment group. In conclusion, Smac could promote the degradation of IAPs, accelerate mitochondrial damage, induce Cyt-c oxidation and Apaf-1 recruitment during postmortem aging of Tibetan sheep meat, thus activating caspase-9/3, facilitating mitochondrial pathway apoptosis and effectively improving Tibetan sheep meat tenderness.

Birinapant in combination with CHK1 or AURKA inhibitors results in selective cell killing in RB-deficient TNBC models and yields durable disease control via apoptosis in vivo. In conclusion, RB loss in TNBC displays an enhanced vulnerability to pro-apoptotic signaling that can enable the effective implementation of new targeted therapeutic strategies.

The loss of USP13 significantly potentiates TNF-α/SMAC mimetic birinapant/pan-caspase inhibitor Z-VAD-FMK (TBZ)-induced necroptosis in CRC cells and diminishes tumor growth in a xenograft model. Thereby, USP13 may serve as a potential therapeutic target for anticancer treatment of CRC.

The constructed 4-gene hypoxia-lactylation prognostic model can effectively predict survival risk in LGG patients. The high-risk group is characterized by activation of pro-tumorigenic pathways, high immune infiltration, and sensitivity to specific targeted drugs. FABP5 + TAMs participate in LGG progression by regulating lipid metabolism and inflammatory responses, representing a potential therapeutic target.

Reducing SMURF1, using a RIPK3 mutant defective in SMURF1-mediated ubiquitination, or overexpressing USP5 enhances necroptosis in leukaemia cells, leading to reduced tumour growth in xenograft models treated with birinapant and emricasan. These findings highlight the opposing regulation of K63-linked polyubiquitination of RIPK3 by SMURF1 and USP5 in necroptosis.

Pharmacologic reprogramming with the SMAC mimetic LCL161 in combination with T-cell-derived cytokines can induce macrophages to phagocytose live cancer cells in mouse models...Unlike mouse macrophages, where a combination of SMAC mimetics with lymphotoxin enhanced phagocytosis, human macrophages were more efficiently polarized to phagocytose live cells by the combination of SMAC mimetics and IFNg. We profiled phagocytic macrophages by transcriptional and proteomic methodologies, uncovering a positive feedback loop of autocrine TNFa production.

Kaempferol acts as a multi-target therapeutic agent in CCA by inducing ER stress, autophagy, and triggering necroptosis when combined with zVAD-FMK and LCL-161, while enhancing immunogenic cell death. These findings support its potential as a novel immunogenic cell death-based treatment strategy for CCA.