A Chimeric SERM–Histone Deacetylase Inhibitor Approach to Breast Cancer Therapy

Abstract

Breast cancer remains a significant cause of death in women and few therapeutic options exist for estrogen receptor negative ER(−) cancers. Epigenetic re-activation of target genes using histone deacetylase (HDAC) inhibitors has been proposed in ER(−) cancers to resensitize to therapy using selective estrogen receptor modulators (SERMs) that are effective in ER(+) cancer treatment. Based upon preliminary studies in ER(+) and ER(−) breast cancer cells treated with combinations of HDAC inhibitors and SERMs, hybrid drugs were designed with computational guidance. Assay for inhibition of four Type I HDAC isoforms and antagonism of estrogenic activity in two cell lines yielded a “SERMostat” with 1–3 μM potency across all targets. The superior hybrid caused significant cell death in ER(−) human breast cancer cells and elicited cell death at the same concentration as the parent SERM in combination treatment and at an earlier time point.

Chimeric HDAC inhibitors: Comprehensive review on the HDAC‐based strategies developed to combat cancer

“…On the other hand, HDAC inhibition has a synergistic effect with the SERMs for breast cancer combat rendering the combination of HDAC inhibitors with tamoxifen and other SERMs as successful strategy that reversed the tamoxifen resistance. This SERM resistance may be acquired via epigenetic silencing of ERs, so the HDAC inhibition found to restore the expression of ERs in such ER‐negative cancer cells in order to sensitize them to tamoxifen again . In 2013, Gryder et al .…”

“…In 2014, Patel et al . developed hybrid compounds targeting both ERs and HDAC by connecting the hydroxamic acid as ZBG to the 2‐phenylbenzo[b]thiophen‐6‐ol scaffold of raloxifen ( 104 ) to yield chimeric cytotoxic agents with SERM activity and inhibiting the HDACs.…”

“…This SERM resistance may be acquired via epigenetic silencing of ERs, so the HDAC inhibition found to restore the expression of ERs in such ER-negative cancer cells in order to sensitize them to tamoxifen again. 101 In 2013, Gryder et al 102 investigated the conjugation of HDAC These findings render the MH to be a successful strategy that can reverse tamoxifen resistance.…”

Synthesis and structure–activity relationships of novel hybrid ferrocenyl compounds based on a bicyclic core skeleton for breast cancer therapy

“…Although overexpression of HDAC1, HDAC6 and HDAC8 have been linked to breast cancer, 46 HDAC1 and HDAC6 have been found to be more critical 26,29. As shown by the data inTable 4, the HDAC inhibition activity was very much dependent on the length of the acid chain of FcOBHS-HDACi…”

“…Indeed, recent observations have shown that dual-acting ER ligand-HDACi conjugates have an improved in vitro therapeutic index and potent anti-cancer activity; [26][27][28][29] yet, they retain some disadvantages. For instance, most benzothiophene scaffold-based hybrid HDAC inhibitors (e.g., compound 7, Figure 2) show little effect on ER transcriptional activity, 29 ethynylestradiol-HDACi conjugates (e.g., compound 8, Figure 2) retain the and Tam-HDACi conjugates (e.g., compound 9, Figure 2) are toxic to the healthy cells. 26 In recent years, bioorganometallic chemistry has attracted active interest in medicinal chemistry, and numerous classes of organometallic compounds have been found application in drug design.…”