Medical Therapies: Aromatase Inhibitors

Bulun, Serdar E.; Attar, Erkut; Gürateş, Bilgin; Chen, You Hong; Tokunaga, Hideki; Monsivais, Diana; Pavone, Mary Ellen

doi:10.1002/9781444398519.ch35

Cited by 2 publications

(3 citation statements)

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“…8,9 AIs have also been effectively used in the treatments of endometriosis, 10 ovarian, 11 and lung 12 cancers. The enzyme has been a subject of intense biochemical and biophysical investigations for the past 40 years.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of estrogen biosynthesis by the third generation aromatase inhibitors (AIs) exemestane (EXM), letrozole (LTZ), and anastrozole (ANZ) (Figure ) is the frontline therapy for postmenopausal estrogen-dependent breast cancer. , AIs have also been effectively used in the treatments of endometriosis, ovarian, and lung cancers. The enzyme has been a subject of intense biochemical and biophysical investigations for the past 40 years. − ,,− The recent crystal structure of aromatase in complex with the natural substrate ASD (androst-4-ene-3,17-dione, Figure ) has provided unprecedented glimpses into the molecular basis for its substrate specificity, reaction mechanism, steroidal passage, vibrational modes, transmembrane integration, and oligomeric state. ,,, This structural insight has prompted the urgency for the incorporation of aromatase specificity into the inhibitors and revitalized new AI discovery research. − The design that exploits the androgen-specific architecture of the active site and interactions exclusive to the substrate-binding pocket is likely to minimize cross-reactivities of the current AIs.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of estrogen biosynthesis by the third generation aromatase inhibitors (AIs) exemestane (EXM), letrozole (LTZ), and anastrozole (ANZ) (Figure 1) is the frontline therapy for postmenopausal estrogen-dependent breast cancer. 8,9 AIs have also been effectively used in the treatments of endometriosis, 10 ovarian, 11 and lung 12 cancers. The enzyme has been a subject of intense biochemical and biophysical investigations for the past 40 years.…”

Section: ■ Introductionmentioning

confidence: 99%

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Novel Aromatase Inhibitors by Structure-Guided Design

et al. 2012

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Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC50 values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC50 values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme–substrate/exemestane complexes. The observed structure–activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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Novel Aromatase Inhibitors by Structure-Guided Design

et al. 2012

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Non-coding RNAs in endometriosis: a narrative review

Panir

Schjenken

Robertson

et al. 2018

Human Reproduction Update

123

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There is a compelling case that microRNAs, long non-coding RNAs and short inhibitory RNAs have the potential to influence endometriosis development and persistence through modulating inflammation, proliferation, angiogenesis and tissue remodelling. Rapid advances in ncRNA biomarker discovery and therapeutics relevant to endometriosis are emerging. Unravelling the significance of ncRNAs in endometriosis will pave the way for new diagnostic tests and identify new therapeutic targets and treatment approaches that have the potential to improve clinical options for women with this disabling condition.

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Medical Therapies: Aromatase Inhibitors

Cited by 2 publications

References 65 publications

Novel Aromatase Inhibitors by Structure-Guided Design

Novel Aromatase Inhibitors by Structure-Guided Design

Non-coding RNAs in endometriosis: a narrative review

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