Discovery of a Novel Class of Dimeric Smac Mimetics as Potent IAP Antagonists Resulting in a Clinical Candidate for the Treatment of Cancer (AZD5582)

Abstract

A series of dimeric compounds based on the AVPI motif of Smac were designed and prepared as antagonists of the inhibitor of apoptosis proteins (IAPs). Optimization of cellular potency, physical properties, and pharmacokinetic parameters led to the identification of compound 14 (AZD5582), which binds potently to the BIR3 domains of cIAP1, cIAP2, and XIAP (IC50 = 15, 21, and 15 nM, respectively). This compound causes cIAP1 degradation and induces apoptosis in the MDA-MB-231 breast cancer cell line at subnanomolar concentrations in vitro. When administered intravenously to MDA-MB-231 xenograft-bearing mice, 14 results in cIAP1 degradation and caspase-3 cleavage within tumor cells and causes substantial tumor regressions following two weekly doses of 3.0 mg/kg. Antiproliferative effects are observed with 14 in only a small subset of the over 200 cancer cell lines examined, consistent with other published IAP inhibitors. As a result of its in vitro and in vivo profile, 14 was nominated as a candidate for clinical development.

Expression of IAP family proteins and its clinical importance in breast cancer patients

“…Additionally, Foster et al demonstrated in breast cancer cell lines that the use of a combination of IAP antagonists with proapoptotic agents promotes apoptosis, suggesting that this combination of drugs could offer a clinical benefit in breast cancer patients [23]. Recently published study by Hennessy et al, conducted in cell lines and in breast cancer patients, indicated that the novel dimeric IAP antagonist -compound 14 (AZD5582) is promising candidate for clinical development as an anticancer agent [25].…”

Targeting the Inhibitor of Apoptosis Protein BIR3 Binding Domains

“…As drawn, the monomeric units of BV6 [81] and SM-164 [83] appear to point away AstraZeneca disclosed a family of P4-P4 compounds that were linked through the P4 amide moity [99]. These studies lead to the nomination of the clinical candidate AZD5582 [100].…”

“…Binding to cIAP1 and cIAP2 induces E3 ubiquitin ligase activity resulting in ubiquination of RIPK1, canonical NF-κB activation, cIAP1 and cIAP2 autoubiquitination, and their subsequent proteasomal degradation [78,79]. Therefore, loss of cIAP1 protein from cellular lysates and clinical samples has served as an effective biomarker during both preclinical and clinical development [1][2][3][4][5][6][7][8]34,35,44,70,95,96,100,110]. As such, both singleagent and combination trials are ongoing.…”

The Discovery of Macrocyclic XIAP Antagonists from a DNA-Programmed Chemistry Library, and Their Optimization To Give Lead Compounds with in Vivo Antitumor Activity

“…Both 15 and 16 have good activity against the type I cancer cell lines, and we observed sub-μM IC 50 values against type II A875 cells. More benefit was observed with L-cyclohexylglycine (17) or L-tert-butylglycine (18) in P2 while retaining L-2-naphthylalanine in P4. Potent binding affinity of these compounds for BIR2 and 3 domains translated into inhibition of both XIAP and cIAP1 BIR2−3 constructs tested in a FPA format.…”