STUDY QUESTION: Does the novel progesterone receptor (PR) modulator BAY 1002670, based on its preclinical pharmacological profile, offer a potential novel treatment option for uterine fibroids? SUMMARY ANSWER: The newly synthesized BAY1002670 has proved to be a very potent, highly selective PR modulator in all in vitro and in vivo pharmacodynamics assays performed: it exhibits marked efficacy in an innovative humanized fibroid disease model, suggesting BAY 1002670 to be a very promising treatment option for uterine fibroids. WHAT IS KNOWN ALREADY: PR inhibiting ligands have shown clinical utility in a range of potential indications and applications. Despite the emergence of the first PR antagonist >30 years ago, no agent of this compound class has been authorized in any indication for long-term application. Among other reasons, suboptimal selectivity and safety profiles of previous candidates have led to discontinuation and modification of development programmes. STUDY, DESIGN, SIZE, DURATION: The preclinical studies include relevant in vitro and in vivo assays to clarify the properties of the PR modulator BAY 1002670 as well as a fibroid xenograft study to show directly the efficacy of BAY 1002670 on the human target tissue. PARTICIPANTS/MATERIAL, SETTING, METHODS: BAY 1002670 was tested for binding and transactivational activity towards different human steroid receptors. Activity of the compound in the corresponding in vivo models (rat, rabbit) was assessed. Furthermore, BAY 1002670 was tested in a disease model for uterine fibroids utilizing primary human tumour tissues as xenograft in immunodeficient mice treated with estradiol (E2) and progesterone (P). MAIN RESULT AND THE ROLE OF CHANCE: BAY1002670 in subnanomolar concentrations exhibits a highly selective binding profile and antagonistic activity for the PR. These properties are also reflected in its action in two progesterone-dependent animal models that assess the termination of pregnancy and endometrial transformation. Favourable selectivity towards other nuclear hormone receptors was demonstrated. No in vivo activity was found at the glucocorticoid, estrogenic and mineralocorticoid receptors with only weak anti-androgenic activity. In a human fibroid xenograft model BAY 1002670 showed a marked dose-dependent reduction of fibroid tumour weight gain of 95% at a dose of 3 mg/kg/day (P < 0.005). LIMITATIONS AND REASON FOR CAUTION: Selectivity and potency of BAY 1002670 have only been determined in vitro and in animal models so far. WIDER IMPLICATIONS OF THE FINDING: The PR modulator BAY 1002670 might offer a treatment option not only for uterine fibroids but also for other gynaecological indications. STUDY FUNDING/COMPETING INTEREST: The studies took place at Bayer Pharma AG. All authors are employees of Bayer Pharma AG. No external funding declared.
STUDY QUESTION: Does the novel progesterone receptor (PR) modulator BAY 1002670, based on its preclinical pharmacological profile, offer a potential novel treatment option for uterine fibroids? SUMMARY ANSWER: The newly synthesized BAY1002670 has proved to be a very potent, highly selective PR modulator in all in vitro and in vivo pharmacodynamics assays performed: it exhibits marked efficacy in an innovative humanized fibroid disease model, suggesting BAY 1002670 to be a very promising treatment option for uterine fibroids. WHAT IS KNOWN ALREADY: PR inhibiting ligands have shown clinical utility in a range of potential indications and applications. Despite the emergence of the first PR antagonist >30 years ago, no agent of this compound class has been authorized in any indication for long-term application. Among other reasons, suboptimal selectivity and safety profiles of previous candidates have led to discontinuation and modification of development programmes. STUDY, DESIGN, SIZE, DURATION: The preclinical studies include relevant in vitro and in vivo assays to clarify the properties of the PR modulator BAY 1002670 as well as a fibroid xenograft study to show directly the efficacy of BAY 1002670 on the human target tissue. PARTICIPANTS/MATERIAL, SETTING, METHODS: BAY 1002670 was tested for binding and transactivational activity towards different human steroid receptors. Activity of the compound in the corresponding in vivo models (rat, rabbit) was assessed. Furthermore, BAY 1002670 was tested in a disease model for uterine fibroids utilizing primary human tumour tissues as xenograft in immunodeficient mice treated with estradiol (E2) and progesterone (P). MAIN RESULT AND THE ROLE OF CHANCE: BAY1002670 in subnanomolar concentrations exhibits a highly selective binding profile and antagonistic activity for the PR. These properties are also reflected in its action in two progesterone-dependent animal models that assess the termination of pregnancy and endometrial transformation. Favourable selectivity towards other nuclear hormone receptors was demonstrated. No in vivo activity was found at the glucocorticoid, estrogenic and mineralocorticoid receptors with only weak anti-androgenic activity. In a human fibroid xenograft model BAY 1002670 showed a marked dose-dependent reduction of fibroid tumour weight gain of 95% at a dose of 3 mg/kg/day (P < 0.005). LIMITATIONS AND REASON FOR CAUTION: Selectivity and potency of BAY 1002670 have only been determined in vitro and in animal models so far. WIDER IMPLICATIONS OF THE FINDING: The PR modulator BAY 1002670 might offer a treatment option not only for uterine fibroids but also for other gynaecological indications. STUDY FUNDING/COMPETING INTEREST: The studies took place at Bayer Pharma AG. All authors are employees of Bayer Pharma AG. No external funding declared.
Authors: Hareesh B Nair; Bindu Santhamma; Naveen K Krishnegowda; Kalarikkal V Dileep; Klaus J Nickisch Journal: PLoS One Date: 2016-03-24 Impact factor: 3.240
Authors: Martin Fritsch; Nicole Schmidt; Ina Gröticke; Anna-Lena Frisk; Christopher S Keator; Markus Koch; Ov D Slayden Journal: PLoS One Date: 2015-11-20 Impact factor: 3.240