2014 EORTC: Induction of apoptosis with a novel dual cIAP1/XIAP antagonist in models of melanoma

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Summary

Inhibitor of apoptosis (IAP) antagonists are being tested in the clinic for the treatment of cancer as they can switch cancer cell TNFα signalling from being pro-survival to being pro-apoptotic, and
relieve the block on effector caspase activation (1,2). Astex has used fragment based-drug discovery to develop a first-in-class, dual XIAP/cIAP1 antagonist (ASTX660), which is non-peptidomimetic,
does not contain an alanine as a warhead and demonstrates prolonged antagonism of both XIAP and cIAP1 in vivo.

Melanoma is a highly aggressive malignancy with an exceptional ability to develop resistance to targeted therapies. Targeting IAP proteins in melanoma is a promising strategy to overcome this
resistance (3), and ASTX660 represents a novel approach because of the enhanced potency against XIAP (4).

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2014 EORTC: Induction of apoptosis with a novel dual cIAP1/XIAP antagonist in models of melanoma

2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models

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Summary

The inhibitor of apoptosis proteins (IAPs) are widely de-regulated in many tumours and contribute to cancer drug resistance. The targeted inhibition of IAPs can switch TNF-alpha
signaling in cancer cells from pro-survival to pro-apoptotic. Therefore, IAPs represent an attractive target for cancer therapy.
The IAP family member cellular IAP1 (cIAP1) is involved in the regulation of TNF-alpha signaling and X-linked IAP (XIAP) directly interacts with and inhibits caspases. IAP family members are
characterized by BIR (baculoviral IAP repeat) domains, to which the endogenous inhibitor of IAPs SMAC (second mitochondria derived activator of caspases) binds. Peptidomimetic compounds
based on the SMAC sequence have been developed, but they show high selectivity for cIAP1. We used our fragment based-drug discovery approach to generate a non-alanine, nonpeptidomimetic
IAP antagonist, which has dual potency for XIAP and cIAP1. Here we describe the characterization of this compound in in vitro and in vivo models of melanoma and breast cancer.
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2014 BACR: Characterisation of the Activity of Potent XIAP/cIAP1 Dual Antagonists in Melanoma Models

2014 CPTT. Novel Small Molecule Antagonists of XIAP and cIAP Generated by Fragment-based Drug Discovery

/in , ,

Summary

The inhibitor of apoptosis proteins (IAPs) are widely de-regulated in many tumours and contribute to cancer drug resistance. The targeted inhibition of IAPs can switch TNF-alpha
signaling in cancer cells from pro-survival to pro-apoptotic. Therefore, IAPs represent an attractive target for cancer therapy.
The IAP family member cellular IAP1 (cIAP1) is involved in the regulation of TNF-alpha signaling and X-linked IAP (XIAP) directly interacts with and inhibits caspases. IAP family members are
characterized by BIR (baculoviral IAP repeat) domains, to which the endogenous inhibitor of IAPs SMAC (second mitochondria derived activator of caspases) binds. Peptidomimetic compounds
based on the SMAC sequence have been developed, but they show high selectivity for cIAP1. We used our fragment based-drug discovery approach to generate a non-alanine, nonpeptidomimetic
IAP antagonist, which has dual potency for XIAP and cIAP1. Here we describe the characterization of this compound in in vitro and in vivo models of melanoma and breast cancer.

View further details below
2014 CPTT. Novel Small Molecule Antagonists of XIAP and cIAP Generated by Fragment-based Drug Discovery