SBIR-STTR Award

During the past decade, the discovery of kisspeptin peptides and their cognate receptor KISS1R (aka GPR54) has expanded our mechanistic understanding of the hypthothalamic-pituitary-gonadal (HPG) axis. The kisspeptin system has been shown to be an integrator of several streams of biological feedback (endocrine, metabolic, circadian) and regulates the pulsatile secretion of GnRH, which subsequently controls the release of the gonadotropins LH and FSH. Gonadotropin activity dictates a host of biological responses, including gonadal development, puberty, fertility, gametogenesis and sex hormone production. Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among women of reproductive age. Infrequent and/or prolonged menstrual periods, aberrant hair growth (due to associated hyperandrogenism), acne and obesity can all occur in women with PCOS. Commonly, menstrual abnormality signals the condition in adolescence, though PCOS may manifest later following unexplained weight gain and/or difficulty becoming pregnant. Current treatments rely on managing the symptoms of the disease rather than the cause. Recent evidence demonstrates that a hallmark of the pathology of PCOS is hyperpulsatility of GnRH secretion. Thus, as the "gatekeeper" of the HPG-axis and GnRH signaling, KISS1R is an attractive new mechanism for treating the cause of PCOS. KISS1R antagonists should dampen GnRH pulsatility and offer the first possibility of treating the disease at the hypothalamic level. To date there are no drug-like, nonpeptide modulators of KISS1R. Our Phase I approach is to develop the pharmacological tools and deploy them in an in vitro assay cascade for the discovery and characterization of drug-like, nonpeptide antagonists of KISS1R. This assay cascade will employ different assays (e.g. whole cell functional, competition binding) such that we will be able to rapidly evaluate nonpeptide compounds and identify those that display insurmountable antagonism and slow dissociation rates from the receptor. We will use this information to guide small molecule medicinal chemistry efforts to characterize a drug-like lead chemical series. We have previously demonstrated that the use of this type of cascade to guide medicinal chemistry efforts can circumvent many common issues that often lead early stage programs astray. If successful, this project will pave the way for the Phase II optimization (pharmacokinetic, pharmacodynamic, and toxicological) and preclinical development of a novel set of KISS1R antagonists capable of being ready for human clinical development for the treatment of PCOS and potentially other reproductive disorders.

Public Health Relevance:
This project entails the development of kisspeptin receptor assays that will be used to guide design and synthesis of novel drug-like compounds for the treatment of polycystic ovary syndrome (PCOS). If successful, this work will provide lead molecules that could be optimized for human clinical trials.

Public Health Relevance Statement:
: This project entails the development of kisspeptin receptor assays that will be used to guide design and synthesis of novel drug-like compounds for the treatment of polycystic ovary syndrome (PCOS). If successful, this work will provide lead molecules that could be optimized for human clinical trials.

Project Terms:
Acne; Address; Adolescence; Affinity; Age; base; Binding (Molecular Function); Biological; Biological Assay; Biological feedback; Cells; Characteristics; Chemicals; Circadian Rhythms; Clinical; clinical application; Clinical Treatment; Clinical Trials; controlled release; Defect; design; Development; Disease; Dissociation; Drug Kinetics; Endocrine; endometriosis; Equilibrium; Evaluation; Fertility; Gametogenesis; Gatekeeping; Goals; Gonadal Steroid Hormones; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; Government; GPR54 gene; Growth; Hair; Hormonal; Hour; Human; Hyperandrogenism; hypothalamic pituitary gonadal axis; Hypothalamic structure; In Vitro; in vitro Assay; in vivo; Kinetics; kisspeptin; Lead; Legal patent; Ligand Binding; Ligands; Literature; Membrane; Menstruation; Metabolic; novel; Obesity; Pathology; peptide analog; Peptides; Permeability; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; pharmacophore; Phase; Phase II Clinical Trials; pituitary gonadal axis; Polycystic Ovary Syndrome; pre-clinical; pregnant; Preparation; Production; programs; Property; Puberty; receptor; Reporting; reproductive; reproductive hormone; research clinical testing; response; second messenger; Second Messenger Systems; Series; Signal Transduction; small molecule; Staging; Stream; Structure; success; Symptoms; System; therapy development; tool; Toxicology; Weight Gain; Woman; Work

During the past decade, the discovery of kisspeptin peptides and their cognate receptor KISS1R has expanded our mechanistic understanding of the hypthothalamic-pituitary-gonadal (HPG) axis. The kisspeptin system has been shown to be an integrator of several streams of biological feedback (endocrine, metabolic, circadian) and regulates the pulsatile secretion of GnRH, which subsequently controls the release of the gonadotropins LH and FSH. Gonadotropin activity dictates a host of biological responses, including gonadal development, puberty, fertility, gametogenesis, and sex hormone production. Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among women of reproductive age. Infrequent and/or prolonged menstrual periods, acne, aberrant hair growth (due to associated hyperandrogenism), insulin resistance, and obesity can all occur in women with PCOS. Commonly, menstrual abnormality signals the onset of the condition in adolescence, though PCOS may manifest later following unexplained weight gain and/or difficulty becoming pregnant. Current treatments rely on managing the symptoms of the disease rather than the cause. Recent evidence demonstrates that a hallmark of the pathology of PCOS is hyperpulsatility of GnRH secretion. Thus, as the "gatekeeper" of the HPG-axis and GnRH pulsatility, KISS1R is an attractive new mechanism for treating the neuroendocrine cause of PCOS. KISS1R antagonists should dampen GnRH pulsatility and offer the first possibility of treating the disease at the hypothalamic level, while minimizing the potential risk of hypoestrogenemia. During our Phase I program, we were able to develop the medicinal chemistry strategy and pharmacologic methodology to determine the activity of KISS1R antagonists. This resulted in non-peptides with good potency and none of the physicochemical liabilities of the only series of previously published antagonists. We were able to extend the goals of our Phase I program to include an initial characterization of selectivity, pharmacokinetics, and pharmacodynamics of a lead molecule. Our Phase II plan is to use pharmacology, receptor structural models and medicinal chemistry to further develop these antagonists in terms of potency, selectivity, oral bioavailability (as well as other drug-like properties), and efficacy in animal models of HPG axis control and pulsatility. If successful, his project will result in the selection of a drug candidate for pre-IND enabling toxicology studies to support first-in-human studies. Ultimately, this molecule would be evaluated in later stage clinical trials as a potential First-In-Class treatment for women with PCOS and other reproductive disorders.

Public Health Relevance Statement:


Public Health Relevance:
This project entails the further development and optimization of kisspeptin receptor antagonists that will be evaluated in models of reproductive axis control. I ultimately successful, this work will provide a drug candidate that will be tested in clinical trias for efficacy in reproductive disorders, especially PCOS.

Project Terms:
Abbreviations; Acne; Address; Adolescence; Animal Model; Bibliography; Binding (Molecular Function); Biological; Biological Assay; Biological Availability; Biological feedback; Characteristics; Circadian Rhythms; Clinical; clinical application; Clinical Trials; Communities; controlled release; Defect; Detection; Development; Disease; Dose; drug candidate; Drug Kinetics; Endocrine; Ensure; Enzymes; Evaluation; Fertility; Gametogenesis; Gatekeeping; Goals; Gonadal Steroid Hormones; Gonadotropins; Government; Growth; Hair; Hormonal; Human; Hyperandrogenism; hypothalamic pituitary gonadal axis; Hypothalamic structure; improved; In Vitro; in vivo; innovation; Insulin Resistance; Intravenous; Ion Channel; KISS1 gene; kisspeptin; Lead; Maximum Tolerated Dose; Menstruation; Metabolic; Methodology; Modeling; Mus; Neurosecretory Systems; novel; novel therapeutics; Obesity; Oral; Pathology; Peptides; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; pharmacodynamic model; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Pituitary Gland; pituitary gonadal axis; Polycystic Ovary Syndrome; pre-clinical; pregnant; Preparation; Production; programs; Property; Puberty; public health relevance; Publishing; Rattus; receptor; reproductive; reproductive axis; reproductive hormone; Research; research clinical testing; response; Risk; Rodent; Safety; Series; Signal Transduction; stable cell line; Staging; Stream; Structural Models; success; Symptoms; System; Testing; tool; Toxic effect; Toxicology; treatment strategy; Weight Gain; Woman; Work