Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation

Abstract

RESULTS Structure Table 1. (Fig. 3). Degradation of cIAP1 and XIAP by SNIPER(ER)s.As observed in studies of many IAP antagonists, SNIPERs in our study rapidly ( Fig. 2a and 3b), consistent with their increased binding affinities for cIAP1 (Table 1). Further, these SNIPER(ER)s reduced XIAP expression in MCF-7 cells after 48 h in a more potent fashion than SNIPER(ER)-87( Fig. 2a). The reduction of XIAP by SNIPER(ER)s was prominent in T47D cells after 48 h, but was weak after 4 h of exposure (Fig. 3b). The difference in the degradation pattern between cIAP1 and XIAP suggests that these IAPs are degraded through a different mechanism, as discussed below. XIAP is required for the ERα degradation by SNIPER(ER)s.We previously reported that XIAP is In vivo protein knockdown activities and antitumor activities of SNIPER(ER)sWe measured the metabolic stabilities of Development of potent SNIPER derivatives against ERα 9MCF-7 cells, but not in T47D cells (Fig. 6).The role of IAPs in cancer cell survival has been suggested in many papers (32,(42)(43)(44)(45)58 Measurement of binding affinities of ERα and IAPsThe bindings between test compounds and cIAP1, cIAP2 or XIAP were determined by

Development of a Potent Protein Degrader against Oncogenic BCR-ABL Protein

“…18,19,21,29) Then, we developed various hybrid molecules by connecting tamoxifen, androgen receptor (AR) antagonists, and KHS-108 to MeBS, which induce the degradation of estrogen receptor (ER), 20,22) AR, 34) and transforming acidic coiled-coil containing protein 3, 23,27) respectively. In addition to these targets, HaloTag-fused proteins 24,26) and huntingtin 32) were successfully degraded by bestatin-based SNIPERs. Thus, selective degradation of target proteins can be attained by hybrid molecules that crosslink target protein and cIAP1.…”

Estrogen Receptors and Ubiquitin Proteasome System: Mutual Regulation

“…Additionally, ERα is rapidly cleaved in the proteasomes in response to the addition of 17β-estradiol to the breast cancer cell culture [99]. Moreover, chimeric molecules termed specific and nongenetic IAP-dependent protein erasers (SNIPERs) induced the ubiquitination and proteasomal degradation of ERα [103].…”

Advances in targeted degradation of endogenous proteins

“…A subgroup of c-IAP PROTACs are commonly referred to as 'specific and non-genetic IAP-dependent protein erasers' (SNIPERs) [101,102]. To date, SNIPERs that target CRABP-2 [101], estrogen receptor alpha (ERα) [103], and transforming acidic coiled-coil-3 (TACC3) [104] have been generated, and in each case, successful degradation of the target protein has been demonstrated. To improve on the cIAP1 ligand-binding affinity, the IAP antagonist LCL161 was chosen as an alternative cIAP1-binding moiety to create a novel SNIPER.…”