eLife (2017)
Update date:2022-08-15
Topics:
Raj, Ganesh V.
Sareddy, Gangadhara Reddy
Ma, Shihong
Lee, Tae-Kyung
Viswanadhapalli, Suryavathi
Li, Rui
Liu, Xihui
Murakami, Shino
Chen, Chien-Cheng
Lee, Wan-Ru
Mann, Monica
Krishnan, Samaya Rajeshwari
Manandhar, Bikash
Gonugunta, Vijay K.
Strand, Douglas
Tekmal, Rajeshwar Rao
Ahn, Jung-Mo
Vadlamudi, Ratna K.
The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly wiTheR and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.
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