Abstract
Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-κB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFα-dependent induction of apoptosis in various cancer cell lines in vitro, whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I-II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1381-91. ©2018 AACR.
Highlights
Evasion of apoptosis is one of the hallmarks of cancer [1] and can be achieved by overexpression of antiapoptotic proteins
ASTX660 potently inhibited the interactions between a second mitochondria-derived activator of caspases (SMAC)-derived peptide and the BIR3 domains of X-linked IAP (XIAP) (BIR3-XIAP) and cIAP1 (BIR3-cIAP1) with IC50 values less than 40 and 12 nmol/L, respectively
The X-ray crystal structure of ASTX660 bound to BIR3-XIAP protein (PDB 5OQW) revealed that this inhibitor binds to the surface of the protein by occupying the same 4 pockets (P1-P4) recognized by the N-terminal sequence of the endogenous ligand SMAC (Fig. 1B) [32, 33]
Summary
Evasion of apoptosis is one of the hallmarks of cancer [1] and can be achieved by overexpression of antiapoptotic proteins. Inhibitor of apoptosis proteins (IAP), such as cellular IAP (cIAP) 1 and 2 and X-linked IAP (XIAP), are key regulators of antiapoptotic and prosurvival signaling pathways; XIAP directly inhibits caspases, whereas cIAPs prevent the formation of proapoptotic signaling complexes. This leads to suppression of apoptosis through both the extrinsic and intrinsic apoptosis pathways [2,3,4]. Their deregulation, through amplification, overexpression, or loss of endogenous antagonists, occurs in various cancers and is associated with tumor growth and poor prognosis, making them attractive targets for anticancer therapy [5].
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