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Reversion of anti-estrogen therapy resistance in breast cancer by inhibitors of IRE1/XBP1 signaling: A structure-activity relationship study

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Dr. Ihab Kabaha

Chronic unfolded protein response (UPR) within the endoplasmic reticulum (ER) is directly correlated with breast cancer drug resistance. Expression of X-box binding protein-1 (Xbp1), a critical component of the UPR signalling correlates with poor clinical responsiveness to tamoxifen, widely used anti-oestrogen therapeutic agent. Xbp-1 is activated by IRE1α RNase (Ire1) by cytoplasmic splicing. In this study, we plan to generate focused libraries employing diverse modifications on the STF-083010 scaffold and salicylaldehyde scaffold to generate novel small molecule inhibitors of Ire1 and thereby inhibit XBP-1 activation. This will be accomplished by classical SAR (stage I) and click chemistry  (Stage II). The small molecule inhibitors to be synthesized in stages I and II consist of diverse structures. The library design will use computational modelling (docking) that utilizes X-ray structure of Ire1 protein/small molecule inhibitor co-crystals and binding affinities. From these computational studies we will select the molecules with high score and synthesize and test them. Our goal is to generate small molecule that will selectively inhibit IRE1α RNase activity in nM concentration. We will assay the activity of these compounds using a tamoxifen-resistant MCF-7 cell line as in vitro model. If, as we hypothesize, our novel STF-083010 analogues specifically block the XBP1 splicing, they will re-establishes tamoxifen sensitivity to resistant MCF-7 cells. Should this be the case we will proceed to xenograft studies. We will test the hypothesis that co-treatment of tamoxifen resistant tumors with an STF-083010 analogue and tamoxifen will significantly delay breast cancer progression in a xenograft mammary tumor model. 

Research Objectives:

  1. To design and select by in silica docking and binding method new analogs of the hit compound STF-083010 and salicylaldehyde to produce potent and selective inhibitors that specifically block XBP1 splicing. The inhibitor candidates  will be selected based on  X-ray crystallographic data of protein co-crystals and binding molecules. STF-083010 and MKC9989 will be used as reference compounds for ranking the candidate molecules. 
  2. To synthesize high-ranking candidate molecules selected from the in silico evaluation.
  3. To develop a potent and selective small molecule inhibitors that block specifically XBP1 splicing, enabling re-establishment of MCF7-TAMR cells’ sensitivity to tamoxifen treatment in vitro.
  4. To demonstrate the synergistic effect of the novel small inhibitor molecules and tamoxifen in controlling breast cancer progression in a xenograft murine mammary cancer model in vivo.

Preliminary results

Our collaborator and former trainee Ming J et al,8 demonstrated significant  increase in the levels of XBP1s both at the mRNA and protein level in a tamoxifen-resistant MCF-7 cell line compared to normal MCF-7 cells. Moreover, they also found that STF-083010 (Figure 1), a novel inhibitor which specifically blocks XBP1 splicing, can re-establish MCF7-TAMR cells’ sensitivity to tamoxifen treatment in vitro. Furthermore, they demonstrated the synergistic effect of STF-083010 and tamoxifen in controlling breast cancer progression in a xenograft murine mammary cancer model. Finally, they investigated XBP1s expression in over 170 breast cancer patients’ samples, and show that XBP1s expression is highly correlated with overall survival in ER+ breast cancer patients, strongly suggesting a potential therapeutic application of XBP1 inhibitors in breast cancer treatment.

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