Glucocorticoid receptor binds to genomic response elements and regulates gene transcription with cell- and gene-specificity. Within a response element, the precise sequence to which the receptor binds has been implicated in directing its structure and activity. We use NMR chemical shift difference mapping to show that non-specific interactions with particular base positions within the binding sequence, such as those of the “spacer”, affect the conformation of distinct regions of the rat glucocorticoid receptor DNA binding domain. These regions include the DNA-binding surface, the “lever arm” and the dimerization interface, suggesting an allosteric pathway that signals between the DNA binding sequence and the associated dimer partner. Disrupting this path by mutating the dimer interface alters sequence-specific conformations, DNA-binding kinetics and transcriptional activity. Our study demonstrates that glucocorticoid receptor dimer partners collaborate to read DNA shape and to direct sequence specific gene activity.

The glucocorticoid receptor dimer interface allosterically transmits sequence-specific DNA signals

Androgen deprivation is the mainstay therapy for metastatic prostate cancer (PCa). Another way of suppressing androgen receptor (AR) signaling is via AR antagonists or antiandrogens. Despite being frequently prescribed in clinical practice, there is conflicting evidence concerning the role of AR antagonists in the management of PCa. In the castration-resistant settings of PCa, docetaxel has been the only treatment option for decades. With recent evidence that castration-resistant PCa is far from AR-independent, there has been an increasing interest in developing new AR antagonists. This review gives a concise overview of the clinically available antiandrogens and the experimental AR antagonists that tackle androgen action with a different approach.

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Androgen receptor antagonists for prostate cancer therapy

Introduction: The progesterone receptor plays an essential role in uterine physiology and reproduction. Selective progesterone receptor modulators (SPRMs) have emerged as a valuable treatment option for hormone dependent conditions like uterine fibroids, which have a major impact on women’s quality of life. SPRMs offer potential for longer term medical treatment and thereby patients may avoid surgical intervention.Areas covered: The authors have reviewed the functional role of the progesterone receptor and its isoforms and their molecular mechanisms of action via genomic and non-genomic pathways. The current knowledge of the interaction of the PR and different SPRMs tested in clinical trials has been reviewed. The authors focused on pharmacological effects of selected SPRMs on the endometrium, their anti-proliferative action, and their suppression of bleeding. Potential underlying molecular mechanisms and the specific histological changes in the endometrium induced by SPRMs (PAEC; Progesterone rec...

https://www.tandfonline.com/doi/pdf/10.1080/14728222.2016.1180368

Selective progesterone receptor modulators (SPRMs): progesterone receptor action, mode of action on the endometrium and treatment options in gynecological therapies.

The immninent dawn of SPRMs in obstetrics and gynecology.

Uterine fibroids (UFs, AKA leiomyoma) are the most important benign neoplastic threat to women's health, with costs up to hundreds of billions of health care dollars worldwide. Uterine fibroids caused morbidities exert a tremendous health toll, impacting the quality of life of women of all ethnicities, especially women of color. Clinical presentations include heavy vaginal bleeding, pelvic pain, bulk symptoms, subfertility, and obstetric complications. Current management strategies heavily lean toward surgical procedures; nonetheless, the choice of treatment is generally subject to patient's age and her desire to preserve future fertility. Women with UF who desire to maintain future fertility potential face a dilemma because of the limited treatment choices that are currently available to help them achieve that goal. Recently, ulipristal acetate the first of the promising family of oral selective progesterone receptor modulators has been approved for UF treatment in Europe, Canada, and several other countries and is under review for possible approval in the USA. In this review article, we discuss recent advances in the management options against UF with a bend toward oral effective long-term treatment alternatives who are particularly suited for those seeking to preserve their future fertility potential. We also explore the transformative concept of primary and secondary UF prevention using these new anti-UF agents. We envision a remarkable shift in the management of UF in future years from surgical/invasive treatment to orally administrated options; clearly, this potential shift will require additional intense clinical research.

Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids.

https://www.jbc.org/content/286/40/35079.full.pdf

Tsang Wai Lam

Papers

Structural Basis for Agonism and Antagonism for a Set of Chemically Related Progesterone Receptor Modulators