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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

https://doi.org/10.1039/D2MD00239F

2022 EHA – Combining the IAP antagonist, tolinapant, with a DNA hypomethylating agent enhances anti-tumour mechanisms in preclinical models of T-cell lymphoma

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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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