Ward, et al; “Epigenetic priming by hypomethylation enhances the immunogenic potential of tolinapant in T-cell lymphoma”; Cancer Research Communications, 2024

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https://doi.org/10.1158/2767-9764.CRC-23-0415

Abstract:

Programmed cell death mechanisms are important for the regulation of tumor development and progression. Evasion of and resistance to apoptosis are significant factors in tumorigenesis and drug resistance. Bypassing apoptotic pathways and eliciting another form of regulated cell death, namely necroptosis, an immunogenic cell death (ICD), may override apoptotic resistance. Here, we present the mechanistic rationale for combining tolinapant, an antagonist of the inhibitor of apoptosis proteins (IAP), with decitabine, a hypomethylating agent (HMA), in T-cell lymphoma (TCL). Tolinapant treatment alone of TCL cells in vitro and in syngeneic in vivo models demonstrated that ICD markers can be upregulated, and we have shown that epigenetic priming with decitabine further enhances this effect. The clinical relevance of ICD markers was confirmed by the direct measurement of plasma proteins from peripheral TCL patients treated with tolinapant. We showed increased levels of necroptosis in TCL lines, along with the expression of cancer-specific antigens (such as cancer testis antigens) and increases in genes involved in interferon signaling induced by HMA treatment, together deliver a strong adaptive immune response to the tumor. These results highlight the potential of a decitabine and tolinapant combination for TCL and could lead to clinical evaluation.

Henderikx et al., “VitroJet: new features and case studies”; Structural Biology. 2024

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Henderikx et al., “VitroJet: new features and case studies”; Structural Biology. 2024

https://journals.iucr.org/d/issues/2024/04/00/ih5005/index.html

Day et al., “Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2)”; J. Med. Chem. 2024

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Day et al., “Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2)”; J. Med. Chem. 2024

https://doi.org/10.1021/acs.jmedchem.3c02118

Woodhead et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2022”; J. Med. Chem. 2024

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Woodhead et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2022”; J. Med. Chem. 2024

https://doi.org/10.1021/acs.jmedchem.3c02070

Townley et al., “Enabling synthesis in fragment-based drug discovery (FBDD): microscale high-throughput optimisation of the medicinal chemist’s toolbox reactions”; RSC Med. Chem.2023

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Townley et al., “Enabling synthesis in fragment-based drug discovery (FBDD): microscale high-throughput optimisation of the medicinal chemist’s toolbox reactions”; RSC Med. Chem.2023

https://doi.org/10.1039/D3MD00495C

Wu et al., “A Diverse Array of Large Capsules Transform in Response to Stimuli”; J. Am. Chem. Soc. 2023

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Wu et al., “A Diverse Array of Large Capsules Transform in Response to Stimuli”; J. Am. Chem. Soc. 2023

https://doi.org/10.1021/jacs.3c02491

Morado et al., “Does a Machine-Learned Potential Perform Better Than an Optimally Tuned Traditional Force Field? A Case Study on Fluorohydrins”; J. Chem. Inf. Model. 2023

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Morado et al., “Does a Machine-Learned Potential Perform Better Than an Optimally Tuned Traditional Force Field? A Case Study on Fluorohydrins”; J. Chem. Inf. Model. 2023

https://pubs.acs.org/doi/10.1021/acs.jcim.2c01510

Taylor et al., “Accelerated Chemical Reaction Optimization using Multi-Task Learning”; ACS Cent. Sci. 2023

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Taylor et al., “Accelerated Chemical Reaction Optimization using Multi-Task Learning”; ACS Cent. Sci. 2023

https://doi.org/10.1021/acscentsci.3c00050

Taylor et al., “A Brief Introduction to Chemical Reaction Optimization”; Chem Rev. 2023

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Taylor et al., A Brief Introduction to Chemical Reaction Optimization; Chem Rev. 2023

https://doi.org/10.1021/acs.chemrev.2c00798

Wu et al., Systematic construction of progressively larger capsules from a fivefold linking pyrrole-based subcomponent. Nature Synthesis 2023

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Wu et al., Systematic construction of progressively larger capsules from a fivefold linking pyrrole-based subcomponent; Nature Synthesis 2023

https://doi.org/10.1038/s44160-023-00276-9