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Dive into the research topics where Michael L. Mohler is active.

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Featured researches published by Michael L. Mohler.


Journal of Medicinal Chemistry | 2009

Nonsteroidal Selective Androgen Receptor Modulators (SARMs): Dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit

Michael L. Mohler; Casey E. Bohl; Amanda Jones; Christopher C. Coss; Ramesh Narayanan; Yali He; Dong Jin Hwang; James T. Dalton; Duane D. Miller

Interest in the development and therapeutic potential of nonsteroidal tissue-selective androgen receptor modulators (SARMs) has increased dramatically within the past decade. Rapidly expanding knowledge of nuclear hormone receptor structure and function and successful proof-of-principle clinical trials with SARMs have revived an almost dormant search for improved androgens. This Award Address attempts to chronicle the landmark discoveries (with emphasis on our work), organize the SARM landscape into clinically relevant bins, and provide insight into the clinical prospects for SARMs. 1.1. Origins of Androgen Use. An early (1889) and unusual experiment in androgen therapy was performed by Charles Edouard Brown-Sequard, age 72. He administered a testicular extract to himself and reported that he felt “increased vigor and capacity for work”. Despite retrospective suggestions that any effect was purely placebo, this report resulted in widespread use of testicular extracts throughout Europe and North America for several decades. Attempts to isolate the active components of testicular extract failed until 1935 when testosterone (17 hydroxy-4-andosten-3-one) was isolated from bull testes. Shortly thereafter, its synthesis was reported. In the same year, extracts of urine from males were shown to cause nitrogen retention, an indicator of anabolic metabolism. Testosterone was the first anabolic androgen to be used clinically, but its use is limited by its androgenicity and pharmacokinetic (PK) issues. 1 In the latter half of the 20th century, the chemical scaffold of testosterone was modified extensively, producing many


Nuclear Receptor Signaling | 2007

Selective androgen receptor modulators in preclinical and clinical development

Ramesh Narayanan; Michael L. Mohler; Casey E. Bohl; Duane D. Miller; James T. Dalton

Androgen receptor (AR) plays a critical role in the function of several organs including primary and accessory sexual organs, skeletal muscle, and bone, making it a desirable therapeutic target. Selective androgen receptor modulators (SARMs) bind to the AR and demonstrate osteo- and myo-anabolic activity; however, unlike testosterone and other anabolic steroids, these nonsteroidal agents produce less of a growth effect on prostate and other secondary sexual organs. SARMs provide therapeutic opportunities in a variety of diseases, including muscle wasting associated with burns, cancer, or end-stage renal disease, osteoporosis, frailty, and hypogonadism. This review summarizes the current standing of research and development of SARMs, crystallography of AR with SARMs, plausible mechanisms for their action and the potential therapeutic indications for this emerging class of drugs.


Medicinal Research Reviews | 2009

Recent and emerging anti‐diabetes targets

Michael L. Mohler; Yali He; Zhongzhi Wu; Dong Jin Hwang; Duane D. Miller

Diabetes is a disease that affects over 150 million people worldwide for which there are multiple oral and injectable medications. Because of trends in obesity and sedentary lifestyles, diabetes rates in both developed and developing countries are increasing at an alarming rate. Current medications are not adequately effective in maintaining long‐term glycemic control in most patients, even when used in combination, leaving diabetics susceptible to developing life threatening and debilitating complications such as cardiovascular disease, blindness, kidney complications, and amputations. Consequently, there is a critical need for more potent pharmacotherapies with novel mechanisms of action. A panel of 20 emerging diabetes targets is presented, and small molecule modulators for each target will be discussed.


Expert Opinion on Therapeutic Patents | 2005

Nonsteroidal tissue selective androgen receptor modulators: a promising class of clinical candidates

Michael L. Mohler; Vipin A. Nair; Dong Jin Hwang; Igor M. Rakov; Renukadevi Patil; Duane D. Miller

The androgen receptor (AR) is a nuclear hormone receptor that, upon binding to testosterone, dihydrotestosterone (DHT) and other endogenous androgens, supports the development, growth and maintenance of masculine features through activation of anabolic and androgenic metabolism. The AR has been demonstrated to be a productive therapeutic target. AR ligands in clinical practice include androgenic steroids, antiandrogenic steroids and antiandrogenic nonsteroidals. Of primary importance for this review are nonsteroidal selective AR modulators (SARMs) that have tissue-specific agonist and/or antagonist activities. The AR has a myriad of peripheral and central functions that can be modulated in a pleiotropic and tissue-specific fashion using the increasingly diverse collection of SARMs discussed herein. This suggests that SARMs will have a high level of clinical utility for a wide variety of health conditions. The patent literature focusing on SARMs is reviewed and reveals multiple chemical classes in various stages of preclinical and clinical development. Emphasis is placed on selected disease states for which SARMs show potential for therapeutic use in clinical practice.


Current Opinion in Supportive and Palliative Care | 2013

Selective androgen receptor modulators for the prevention and treatment of muscle wasting associated with cancer.

James T. Dalton; Ryan P. Taylor; Michael L. Mohler; Mitchell S. Steiner

Purpose of reviewThis review highlights selective androgen receptor modulators (SARMs) as emerging agents in late-stage clinical development for the prevention and treatment of muscle wasting associated with cancer. Recent findingsMuscle wasting, including a loss of skeletal muscle, is a cancer-related symptom that begins early in the progression of cancer and affects a patients quality of life, ability to tolerate chemotherapy, and survival. SARMs increase muscle mass and improve physical function in healthy and diseased individuals, and potentially may provide a new therapy for muscle wasting and cancer cachexia. SARMs modulate the same anabolic pathways targeted with classical steroidal androgens, but within the dose range in which expected effects on muscle mass and function are seen androgenic side-effects on prostate, skin, and hair have not been observed. Unlike testosterone, SARMs are orally active, nonaromatizable, nonvirilizing, and tissue-selective anabolic agents. SummaryRecent clinical efficacy data for LGD-4033, MK-0773, MK-3984, and enobosarm (GTx-024, ostarine, and S-22) are reviewed. Enobosarm, a nonsteroidal SARM, is the most well characterized clinically, and has consistently demonstrated increases in lean body mass and better physical function across several populations along with a lower hazard ratio for survival in cancer patients. Completed in May 2013, results for the Phase III clinical trials entitled Prevention and treatment Of muscle Wasting in patiEnts with Cancer1 (POWER1) and POWER2 evaluating enobosarm for the prevention and treatment of muscle wasting in patients with nonsmall cell lung cancer will be available soon, and will potentially establish a SARM, enobosarm, as the first drug for the prevention and treatment of muscle wasting in cancer patients.


Expert Opinion on Therapeutic Patents | 2007

Dissociated non-steroidal glucocorticoids: tuning out untoward effects

Michael L. Mohler; Yali He; Zhongzhi Wu; Seoung Soo Hong; Duane D. Miller

The endogenous glucocorticoid (GC), cortisol, is involved in maintaining homeostatic balance in glucose regulation and immune response while allowing stress adaptation. The glucocorticoid receptor (GR) is required to maintain life and is the target of numerous FDA-approved drugs. Synthetic steroidal GCs are useful in a plethora of conditions characterized by excessive inflammatory or immune responses. Unfortunately, the GCs used at present have potentially dose-limiting and debilitating side effects, some of which derive from the glucose regulatory role of GCs. Consequently, there is a great need to find agents which preserve the potent immune effects without the side effects. This manuscript reviews the existing patent literature on these intensely sought non-steroidal agents that dissociate the therapeutic from metabolic effects, or specifically retain certain GR target effects with attenuated untoward effects. The chemical classes and underlying mechanisms (when known) for these non-steroidal GCs are discussed.


Bioorganic & Medicinal Chemistry Letters | 2008

Effect of B-ring substitution pattern on binding mode of propionamide selective androgen receptor modulators

Casey E. Bohl; Zengru Wu; Jiyun Chen; Michael L. Mohler; Jun Yang; Dong Jin Hwang; Suni M. Mustafa; Duane D. Miller; Charles E. Bell; James T. Dalton

Selective androgen receptor modulators (SARMs) are essentially prostate sparing androgens, which provide therapeutic potential in osteoporosis, male hormone replacement, and muscle wasting. Herein we report crystal structures of the androgen receptor (AR) ligand-binding domain (LBD) complexed to a series of potent synthetic nonsteroidal SARMs with a substituted pendant arene referred to as the B-ring. We found that hydrophilic B-ring para-substituted analogs exhibit an additional region of hydrogen bonding not seen with steroidal compounds and that multiple halogen substitutions affect the B-ring conformation and aromatic interactions with Trp741. This information elucidates interactions important for high AR binding affinity and provides new insight for structure-based drug design.


PLOS ONE | 2013

Discovery and Preclinical Characterization of Novel Small Molecule TRK and ROS1 Tyrosine Kinase Inhibitors for the Treatment of Cancer and Inflammation

Ramesh Narayanan; Muralimohan Yepuru; Christopher C. Coss; Zhongzhi Wu; Matthew N. Bauler; Christina M. Barrett; Michael L. Mohler; Yun Wang; Juhyun Kim; Linda M. Snyder; Yali He; Nelson Levy; Duane D. Miller; James T. Dalton

Receptor tyrosine kinases (RTKs), in response to their growth factor ligands, phosphorylate and activate downstream signals important for physiological development and pathological transformation. Increased expression, activating mutations and rearrangement fusions of RTKs lead to cancer, inflammation, pain, neurodegenerative diseases, and other disorders. Activation or over-expression of ALK, ROS1, TRK (A, B, and C), and RET are associated with oncogenic phenotypes of their respective tissues, making them attractive therapeutic targets. Cancer cDNA array studies demonstrated over-expression of TRK-A and ROS1 in a variety of cancers, compared to their respective normal tissue controls. We synthesized a library of small molecules that inhibit the above indicated RTKs with picomolar to nanomolar potency. The lead molecule GTx-186 inhibited RTK-dependent cancer cell and tumor growth. In vitro and in vivo growth of TRK-A-dependent IMR-32 neuroblastoma cells and ROS1-overexpressing NIH3T3 cells were inhibited by GTx-186. GTx-186 also inhibited inflammatory signals mediated by NFκB, AP-1, and TRK-A and potently reduced atopic dermatitis and air-pouch inflammation in mice and rats. Moreover, GTx-186 effectively inhibited ALK phosphorylation and ALK-dependent cancer cell growth. Collectively, the RTK inhibitor GTx-186 has a unique kinase profile with potential to treat cancer, inflammation, and neuropathic pain.


Expert Opinion on Therapeutic Patents | 2007

Non-steroidal glucocorticoid receptor antagonists: the race to replace RU-486 for anti-glucocorticoid therapy

Michael L. Mohler; Yali He; Zhongzhi Wu; Seoung Soo Hong; Duane D. Miller

The endogenous glucocorticoid, cortisol, elevates blood glucose and suppresses the immune system. Glucocorticoid (GC) levels rapidly increase in response to physiologic and mental stress, thereby allowing stress adaptation. Unfortunately, the GC response can be excessive, especially under stressful conditions for the organism. The resulting hypercortisolemia is associated with a cluster of symptoms called Cushing’s syndrome, a serious and potentially fatal illness involving hyperglycemia, hypertension, osteoporosis, muscle atrophy and fat maldistribution, as well as psychoses and immunosuppresion. Several disease states, such as diabetes and Cushing’s, would benefit from blocking the actions of endogenous cortisol. The only glucocorticoid receptor (GR) antagonist available in the clinic is the steroid mifepristone (RU-486), whose primary potency is antigestagenic, making its utility as a GR antagonist limited. This manuscript reviews the current patent literature on selective non-steroidal GR antagonists.


Expert Opinion on Therapeutic Patents | 2012

Androgen receptor antagonists: A patent review (2008 - 2011)

Michael L. Mohler; Christopher C. Coss; Charles Duke; Shivaputra Patil; Duane D. Miller; James T. Dalton

Introduction: Androgen receptor (AR) antagonists are predominantly used as chemical castration to treat prostate cancer (i.e., in conjunction with androgen deprivation therapy (ADT)). Unfortunately, castration-resistant prostate cancer (CRPC) typically develops that is refractory to targeted therapy. Insights into CRPC biology have led to the emergence of a promising clinical candidate MDV3100 (Figure 2) and a resurgence in this field. A pipeline of preclinical competitive (C-terminally directed) antagonists was discovered using a variety of innovative screening paradigms. Some inhibit nuclear translocation, selectively downregulate or degrade AR (SARD), antagonize wild-type and escape mutant AR (pan-antagonists) and/or antagonize AR target organs in vivo. Separately, the N-terminal domain has emerged as a promising novel target for noncompetitive antagonists. Areas covered: AR antagonists whose patents published between 2008 and 2011 are reviewed. Antagonists are organized based on the screening paradigm reported as discussed above. Expert opinion: Novel mechanisms provide a more informed basis for selecting a competitive antagonist; however, high potency and favorable in vivo properties remain paramount. Noncompetitive antagonists have theoretical advantages suggestive of improved clinical efficacy, but no clinical proof of concept as of yet.

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Dong Jin Hwang

University of Tennessee Health Science Center

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Christina M. Barrett

University of Tennessee Health Science Center

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