Rees et al., “Introduction to the themed collection on fragment-based drug discovery”; RSC Med. Chem 2022
Rees et al., “Introduction to the themed collection on fragment-based drug discovery”; RSC Med. Chem 2022
Walsh et al., “Fragment-to-Lead Medicinal Chemistry Publications in 2021”; J Med Chem 2023
Walsh et al., ““Fragment-to-Lead Medicinal Chemistry Publications in 2021””; J Med Chem 2023
Martins et al., “A commentary on the use of pharmacoenhancers in the pharmaceutical industry and the implication for DMPK drug discovery strategies”; Xenobiotica 2022
Martins et al., “A commentary on the use of pharmacoenhancers in the pharmaceutical industry and the implication for DMPK drug discovery strategies”; Xenobiotica 2022
Chan et al., “A multilevel generative framework with hierarchical self-contrasting for bias control and transparency in structure-based ligand design”; Nat. Mach. Intell. 2022
Chan et al., “A multilevel generative framework with hierarchical self-contrasting for bias control and transparency in structure-based ligand design”; Nat. Mach. Intell. 2022
Jones et al., “Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates”; RSC Medicinal Chemistry, Oct 2022
Jones et al., “Exploration of piperidine 3D fragment chemical space: synthesis and 3D shape analysis of fragments derived from 20 regio- and diastereoisomers of methyl substituted pipecolinates”; RSC Medicinal Chemistry, Oct 2022
2022 EHA – Combining the IAP antagonist, tolinapant, with a DNA hypomethylating agent enhances anti-tumour mechanisms in preclinical models of T-cell lymphoma
Introduction
Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of cIAP1, cIAP2 and XIAP 1, 2, and has demonstrated immunomodulatory properties in pre-clinical models of T cell lymphoma (TCL) 3. In an ongoing Phase 2 trial (NCT02503423), tolinapant has shown activity against highly pre-treated peripheral and cutaneous T-cell lymphoma 4.
Hypomethylating agents (HMAs) have also shown clinical responses in some subsets of PTCL 5, 6, suggesting thar reduction of methylation can deliver efficacy in PTCL. In addition, HMAs and IAP antagonists show immunomodulatory anti-cancer potential in pre-clinical studies.
Here we have investigated the potential for HMA-induced reversal of epigenetic silencing or altered cell signalling to promote the induction of immunogenic forms of cell death (ICD), such as necroptosis, driven by tolinapant treatment in pre-clinical models of T-cell lymphoma (TCL).
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