TY - JOUR
T1 - Activators of the Anticipatory Unfolded Protein Response with Enhanced Selectivity for Estrogen Receptor Positive Breast Cancer
AU - Boudreau, Matthew W.
AU - Mulligan, Michael P.
AU - Shapiro, David J.
AU - Fan, Timothy M.
AU - Hergenrother, Paul J.
N1 - Funding Information:
We would like to thank the Roy J. Carver Biotechnology Center, Metabolomics (UIUC) and Dr. Lucas Li for LC–MS/MS analyses, T. Woods for X-ray crystal structure determination (George L. Clark X-Ray Facility and 3M Materials Laboratory), L. Dirikolu for calculating pharmacokinetic parameters. We thank the University of Illinois and the Cancer Center at Illinois (CCIL) for funding this work. M.W.B. and M.P.M. are members of the NIH Chemistry-Biology Interface Training Program (T32-GM136629). M.W.B. was an ACS Medicinal Chemistry Predoctoral Fellow and is now supported by an NCI F99 predoctoral fellowship (F99-CA253731).
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/3/10
Y1 - 2022/3/10
N2 - Approximately 75% of breast cancers are estrogen receptor alpha-positive (ERα+), and targeting ERα directly with ERα antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO, a compound that induces ERα-dependent cancer cell death through a mechanism distinct from clinically approved ERα drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ERα+ tumor models. While ErSO has promise as a new drug, it has effects on ERα-negative (ERα−) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ERα+ and ERα- cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has enhanced selectivity for ERα+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ERα+ cancers.
AB - Approximately 75% of breast cancers are estrogen receptor alpha-positive (ERα+), and targeting ERα directly with ERα antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO, a compound that induces ERα-dependent cancer cell death through a mechanism distinct from clinically approved ERα drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ERα+ tumor models. While ErSO has promise as a new drug, it has effects on ERα-negative (ERα−) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ERα+ and ERα- cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has enhanced selectivity for ERα+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ERα+ cancers.
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U2 - 10.1021/acs.jmedchem.1c01730
DO - 10.1021/acs.jmedchem.1c01730
M3 - Article
C2 - 35080871
AN - SCOPUS:85124167771
SN - 0022-2623
VL - 65
SP - 3894
EP - 3912
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -