Complex tissue-specific and cell-specific signaling by the estrogen receptor (ER) frequently leads to the development of resistance to endocrine therapy for breast cancer. Pure ER antagonists, which completely lack tissue-specific agonist activity, hold promise for preventing and treating endocrine resistance, however an absence of structural information hinders the development of novel candidates. Here we synthesize a small panel of benzopyrans with variable side chains to identify pure antiestrogens in a uterotrophic assay. We identify OP-1074 as a pure antiestrogen and a selective ER degrader (PA-SERD) that is efficacious in shrinking tumors in a tamoxifen-resistant xenograft model. Biochemical and crystal structure analyses reveal a structure activity relationship implicating the importance of a stereospecific methyl on the pyrrolidine side chain of OP-1074, particularly on helix 12.
Abundant links between the gut microbiota and human health indicate that modification of bacterial function could be a powerful therapeutic strategy. The inaccessibility of the gut and inter-connections between gut bacteria and the host make it difficult to precisely target bacterial functions without disrupting the microbiota and/or host physiology. Herein we describe a multidisciplinary approach to modulate the expression of a specific bacterial gene within the gut by oral administration. We demonstrate that an engineered temperate phage λ expressing a programmable dCas9 represses a targeted E. coli gene in the mammalian gut. To facilitate phage administration while minimizing disruption to host processes, we develop an aqueous-based encapsulation formulation with a microbiota-based release mechanism and show that it facilitates oral delivery of phage in vivo. Finally we combine these technologies and show that bacterial gene expression in the mammalian gut can be precisely modified in situ with a single oral dose.
25Abundant links between the gut microbiota and human health indicate that the modification of bacterial 26 function could be a powerful therapeutic strategy. The inaccessibility of the gut and inter-connections 27 between gut bacteria and the host make it difficult to precisely target bacterial functions without disrupting 28 the microbiota and/or host physiology. Herein we describe a multidisciplinary approach to modulate the 29 expression of a specific bacterial gene within the gut by oral administration. We first demonstrate that an 30 engineered temperate phage l expressing a programmable dCas9 represses a targeted E. coli gene in 31 the mammalian gut. To facilitate phage administration while minimizing disruption to host processes, we 32 develop an aqueous-based encapsulation formulation with a microbiota-based release mechanism and 33 show that it facilitates the oral delivery of phage in vivo. Finally we combine these technologies and show 34 that bacterial gene expression in the mammalian gut can be precisely modified in situ with a single oral 35 dose. 36 37 38 Introduction 1 The gut microbiome has numerous associations with human health. 1 This bacterial community contains 2 hundreds of densely colonizing species with a composition that varies along the gastrointestinal tract, 3 between individuals, and over time. 2 The complexity of this ecosystem makes it challenging to precisely 4 target specific bacteria without unintended impacts to the microbiota. 3 To enable the interrogation and 5 therapeutic modification of microbial interactions with the host, generalizable tools are needed, especially 6 ones capable of modifying specific bacterial functions while minimizing disruption to non-targeted genes, 7 microbes, and host physiology.8Multiple biological barriers preclude the efficient modification of bacterial processes within the gut. Oral 9 delivery is the preferable approach but remains challenging because of the acidity and proteases in the 10 upper gastrointestinal tract. 4 Neutralization of these natural physiological barriers can be disruptive and 11 has been associated with increased secretion due to feedback mechanisms, 5 susceptibility to enteric 12 pathogens, 6 and a reduced bacterial diversity in the gut. 7 Variability in meal timing, intestinal motility and 13 individual-specific physiological conditions can further complicate the efficacy of oral delivery 14 formulations. 8 Even if these barriers can be overcome, the nature of the microbiota itself, with a dense 15 colonization of competing species, makes the specific and durable modification of bacteria challenging. 16 Phages are capable of targeting specific bacteria even among a complex consortia. With the prevalence 17 of antibiotic resistant infections, there has been increasing interest in lytic phages for their ability to kill 18 cognate bacteria during phage propagation. Temperate phages, however, have been of less interest 19therapeutically because they do not primarily pursue lysis and can integrate themselves into the bacterial...
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