Summary

Paclitaxel-mediated secretion of inflammatory mediators, including TNFα, potentially creates paracrine and autocrine loops that can contribute to survival and reduction of paclitaxel-induced apoptosis in cancer cells.

One of the mechanisms of cancer cell survival is the expression of inhibitor of apoptosis proteins (IAPs). Cellular IAP (cIAP) is involved in inflammatory pro-survival NF-B activation, blocking the activation of the effector caspases 3 and 7, while X-linked IAP (XIAP) directly binds the effector caspases 3, 7 and 9, inhibiting the full activation of the apoptosis pathway.

ASTX660, a fragment-derived small molecule that is orally bioavailable, is a dual antagonist of cIAP and XIAP (Chessari 2014). Its inhibitory activity has been demonstrated in preclinical models of melanoma and other types of cancer, in which inflammation was present. It is currently being investigated in a single-agent Phase I/II clinical trial in patients with advanced solid tumors and lymphomas (NCT02503423).

Here, we characterize the activity of ASTX660 in preclinical models of triple-negative breast cancer (TNBC) as a single agent and in combination with paclitaxel whose inflammatory properties are hypothesized to sensitize the cells to ASTX660.

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AACR: Dual IAP Antagonist, ASTX660, Increases Anti-tumor Activity of Paclitaxel in TNBC Models

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

2013 RSC/SCI. Fragment Based Drug Discovery of a Potent Dual Antagonist of XIAP and cIAP1

2013 AACR: AT-IAP, a dual cIAP1 and XIAP antagonist with oral antitumor activity in melanoma models

2012 EORTC: Characterization of a Potent XIAP & cIAP1 Dual Antagonist in Melanoma and Leukemia