1 research outputs found
Birinapant, a Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and Hematological Malignancies
Birinapant (<b>1</b>) is a
second-generation bivalent antagonist
of IAP proteins that is currently undergoing clinical development
for the treatment of cancer. Using a range of assays that evaluated
cIAP1 stability and oligomeric state, we demonstrated that <b>1</b> stabilized the cIAP1-BUCR (BIR3-UBA-CARD-RING) dimer and promoted
autoubiquitylation of cIAP1 in vitro. Smac-mimetic <b>1</b>-induced
loss of cIAPs correlated with inhibition of TNF-mediated NF-κB
activation, caspase activation, and tumor cell killing. Many first-generation
Smac-mimetics such as compound <b>A</b> (<b>2</b>) were
poorly tolerated. Notably, animals that lack functional cIAP1, cIAP2,
and XIAP are not viable, and <b>2</b> mimicked features of triple
IAP knockout cells in vitro. The improved tolerability of <b>1</b> was associated with (i) decreased potency against cIAP2 and affinity
for XIAP BIR3 and (ii) decreased ability to inhibit XIAP-dependent
signaling pathways. The P<sub>2</sub>′ position of <b>1</b> was critical to this differential activity, and this improved tolerability
has allowed <b>1</b> to proceed into clinical studies