RESUMO
Heterobifunctional chimeric degraders are a class of ligands that recruit target proteins to E3 ubiquitin ligases to drive compound-dependent protein degradation. Advancing from initial chemical tools, protein degraders represent a mechanism of growing interest in drug discovery. Critical to the mechanism of action is the formation of a ternary complex between the target, degrader and E3 ligase to promote ubiquitination and subsequent degradation. However, limited insights into ternary complex structures exist, including a near absence of studies on one of the most widely co-opted E3s, cellular inhibitor of apoptosis 1 (cIAP1). In this work, we use a combination of biochemical, biophysical and structural studies to characterize degrader-mediated ternary complexes of Bruton's tyrosine kinase and cIAP1. Our results reveal new insights from unique ternary complex structures and show that increased ternary complex stability or rigidity need not always correlate with increased degradation efficiency.
Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Proteínas Inibidoras de Apoptose/genética , Cromatografia em Gel , Reagentes de Ligações Cruzadas , Humanos , Cinética , Modelos Moleculares , Ressonância Magnética Nuclear Biomolecular , Conformação Proteica , Proteólise , Espectrometria de Massas por Ionização por Electrospray , Ubiquitina-Proteína Ligases , Ubiquitinação , Difração de Raios XRESUMO
Targeted protein degradation has emerged from the chemical biology toolbox as one of the most exciting areas for novel therapeutic development across the pharmaceutical industry. The ability to induce the degradation, and not just inhibition, of target proteins of interest (POIs) with high potency and selectivity is a particularly attractive property for a protein degrader therapeutic. However, the physicochemical properties and mechanism of action for protein degraders can lead to unique pharmacokinetic (PK) and pharmacodynamic (PD) properties relative to traditional small molecule drugs, requiring a shift in perspective for translational pharmacology. In this review, we provide practical insights for building the PK-PD understanding of protein degraders in the context of translational drug development through the use of quantitative mathematical frameworks and standard experimental assays. Published datasets describing protein degrader pharmacology are used to illustrate the applicability of these insights. The learnings are consolidated into a translational PK-PD roadmap for targeted protein degradation that can enable a systematic, rational design workflow for protein degrader therapeutics.
Assuntos
Modelos Biológicos , ProteóliseRESUMO
Bispecific protein degraders (BPDs) engage the ubiquitin-proteasome system (UPS) to catalytically degrade intracellular proteins through the formation of ternary complexes with the target protein and E3 ubiquitin ligases. Here, we describe the development of a mechanistic modeling framework for BPDs that includes the reaction network governing ternary complex formation and degradation via the UPS. A critical element of the model framework is a multi-step process that results in a time delay between ternary complex formation and protein degradation, thereby balancing ternary complex stability against UPS degradation rates akin to the kinetic proofreading concept that has been proposed to explain the accuracy and specificity of biological processes including protein translation and T cell receptor signal transduction. Kinetic proofreading likely plays a central role in the cell's ability to regulate substrate recognition and degradation by the UPS, and the model presented here applies this concept in the context of a quantitative pharmacokinetic (PK)-pharmacodynamic (PD) framework to inform the design of potent and selective BPDs.
Assuntos
Desenho de Fármacos , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Ubiquitina/agonistas , Simulação por Computador , Humanos , Modelos Biológicos , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Proteolysis targeting chimeras (PROTACs) are heterobifunctional small molecules that simultaneously bind to a target protein and an E3 ligase, thereby leading to ubiquitination and subsequent degradation of the target. They present an exciting opportunity to modulate proteins in a manner independent of enzymatic or signaling activity. As such, they have recently emerged as an attractive mechanism to explore previously "undruggable" targets. Despite this interest, fundamental questions remain regarding the parameters most critical for achieving potency and selectivity. Here we employ a series of biochemical and cellular techniques to investigate requirements for efficient knockdown of Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase essential for B cell maturation. Members of an 11-compound PROTAC library were investigated for their ability to form binary and ternary complexes with BTK and cereblon (CRBN, an E3 ligase component). Results were extended to measure effects on BTK-CRBN cooperative interactions as well as in vitro and in vivo BTK degradation. Our data show that alleviation of steric clashes between BTK and CRBN by modulating PROTAC linker length within this chemical series allows potent BTK degradation in the absence of thermodynamic cooperativity.
Assuntos
Proteínas Tirosina Quinases/metabolismo , Proteólise , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação , Tirosina Quinase da Agamaglobulinemia , Animais , Células Cultivadas , Ligantes , Poliubiquitina/metabolismo , Ratos , TermodinâmicaRESUMO
The drugable proteome is limited by the number of functional binding sites that can bind small molecules and respond with a therapeutic effect. Orthosteric and allosteric modulators of enzyme function or receptor signaling are well-established mechanisms of drug action. Drugs that perturb protein-protein interactions have only recently been launched. This approach is more difficult due to the extensive contact surfaces that must be perturbed antagonistically. Compounds that promote novel protein-protein interactions promise to dramatically expand opportunities for therapeutic intervention. This approach is precedented with natural products (rapamycin, FK506, sanglifehrin A), synthetic small molecules (thalidomide and IMiD derivatives) and indisulam analogues.
Assuntos
Adesivos/farmacologia , Produtos Biológicos/farmacologia , Regulação Alostérica/efeitos dos fármacos , Descoberta de Drogas , Humanos , Ligantes , Ligação Proteica , Proteólise , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
The concept of target-specific covalent enzyme inhibitors appears attractive from both an efficacy and a selectivity viewpoint considering the potential for enhanced biochemical efficiency associated with an irreversible mechanism. Aside from potential safety concerns, clearance prediction of covalent inhibitors represents a unique challenge due to the inclusion of nontraditional metabolic pathways of direct conjugation with glutathione (GSH) or via GSH S-transferase-mediated processes. In this article, a novel pharmacokinetic algorithm was developed using a series of Pfizer kinase selective acrylamide covalent inhibitors based on their in vitro-in vivo extrapolation of systemic clearance in rats. The algorithm encompasses the use of hepatocytes as an in vitro model for hepatic clearance due to oxidative metabolism and GSH conjugation, and the use of whole blood as an in vitro surrogate for GSH conjugation in extrahepatic tissues. Initial evaluations with clinical covalent inhibitors suggested that the scaling algorithm developed from rats may also be useful for human clearance prediction when species-specific parameters, such as hepatocyte and blood stability and blood binding, were considered. With careful consideration of clearance mechanisms, the described in vitro-in vivo extrapolation approach may be useful to facilitate candidate optimization, selection, and prediction of human pharmacokinetic clearance during the discovery and development of targeted covalent inhibitors.
Assuntos
Hepatócitos/metabolismo , Microssomos Hepáticos/metabolismo , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Plasma/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Algoritmos , Animais , Avaliação Pré-Clínica de Medicamentos , Glutationa/metabolismo , Humanos , Técnicas In Vitro , Masculino , Taxa de Depuração Metabólica , Camundongos Endogâmicos C57BL , Preparações Farmacêuticas/sangue , Valor Preditivo dos Testes , Ligação Proteica , Inibidores de Proteínas Quinases/sangue , Ratos , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
Kinases are principal components of signal transduction pathways and the focus of intense basic and drug discovery research. Irreversible inhibitors that covalently modify non-catalytic cysteines in kinase active sites have emerged as valuable probes and approved drugs. Many protein classes, however, have functional cysteines, and therefore understanding the proteome-wide selectivity of covalent kinase inhibitors is imperative. Here, we accomplish this objective using activity-based protein profiling coupled with quantitative MS to globally map the targets, both specific and nonspecific, of covalent kinase inhibitors in human cells. Many of the specific off-targets represent nonkinase proteins that, notably, have conserved active site cysteines. We define windows of selectivity for covalent kinase inhibitors and show that, when these windows are exceeded, rampant proteome-wide reactivity and kinase target-independent cell death conjointly occur. Our findings, taken together, provide an experimental road map to illuminate opportunities and surmount challenges for the development of covalent kinase inhibitors.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteoma/genética , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisteína/química , Genes erbB-1/genética , Humanos , Cinética , Piperidinas , Proteínas Quinases/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
More than half of the ~20,000 protein-encoding human genes have at least one paralog. Chemical proteomics has uncovered many electrophile-sensitive cysteines that are exclusive to a subset of paralogous proteins. Here, we explore whether such covalent compound-cysteine interactions can be used to discover ligandable pockets in paralogs that lack the cysteine. Leveraging the covalent ligandability of C109 in the cyclin CCNE2, we mutated the corresponding residue in paralog CCNE1 to cysteine (N112C) and found through activity-based protein profiling (ABPP) that this mutant reacts stereoselectively and site-specifically with tryptoline acrylamides. We then converted the tryptoline acrylamide-N112C-CCNE1 interaction into a NanoBRET-ABPP assay capable of identifying compounds that reversibly inhibit both N112C- and WT-CCNE1:CDK2 complexes. X-ray crystallography revealed a cryptic allosteric pocket at the CCNE1:CDK2 interface adjacent to N112 that binds the reversible inhibitors. Our findings thus provide a roadmap for leveraging electrophile-cysteine interactions to extend the ligandability of the proteome beyond covalent chemistry.
RESUMO
Despite several advantages of covalent inhibitors (such as increased biochemical efficiency, longer duration of action on the target, and lower efficacious doses) over their reversible binding counterparts, there is a reluctance to use covalent inhibitors as a drug design strategy in pharmaceutical research. This reluctance is due to their anticipated reactions with nontargeted macromolecules. We hypothesized that there may be a threshold limit for nonspecific covalent binding, below which a covalent binding drug may be less likely to cause toxicity due to irreversible binding to off-target macromolecules. Estimation of in vivo covalent binding burden from in vitro data has previously been used as an approach to distinguish those agents more likely to cause toxicity (e.g., hepatotoxicity) via metabolic activation to reactive metabolites. We have extended this approach to nine covalent binding drugs to determine in vitro covalent binding burden. In vitro covalent binding burden was determined by incubating radiolabeled drugs with pooled human hepatocytes. These data were scaled to an estimate of in vivo covalent binding burden by combining the in vitro data with daily dose. Scaled in vivo daily covalent binding burden of marketed covalent drugs was found to be under 10 mg/day, which is in agreement with previously reported threshold value for metabolically activated reversible drugs. Covalent binding was also compared to the intrinsic reactivities of the covalent inhibitors assessed using nucleophiles glutathione and N-α-acetyl lysine. The intrinsic reactivity did not correlate with observed in vitro covalent binding, which demonstrated that the intrinsic reactivity of the electrophilic groups of covalent drugs does not exclusively account for the extent of covalent binding. The ramifications of these findings for consideration of using a covalent strategy in drug design are discussed.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Hepatócitos/efeitos dos fármacos , Preparações Farmacêuticas/química , Adamantano/análogos & derivados , Adamantano/química , Adamantano/metabolismo , Adamantano/toxicidade , Aspirina/química , Aspirina/metabolismo , Aspirina/toxicidade , Radioisótopos de Carbono/química , Células Cultivadas , Glutationa/química , Glutationa/metabolismo , Meia-Vida , Hepatócitos/metabolismo , Humanos , Lactonas/química , Lactonas/metabolismo , Lactonas/toxicidade , Lisina/química , Lisina/metabolismo , Nitrilas/química , Nitrilas/metabolismo , Nitrilas/toxicidade , Orlistate , Preparações Farmacêuticas/metabolismo , Pirrolidinas/química , Pirrolidinas/metabolismo , Pirrolidinas/toxicidade , Trítio/química , VildagliptinaRESUMO
A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC(50): 926 nM), potent mGluR5 NAMs showing excellent potencies (IC(50)s<50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (K(i): 21 nM) and antagonism (IC(50): 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk).
Assuntos
Benzamidas/química , Piridinas/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Animais , Transtornos de Ansiedade/tratamento farmacológico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Modelos Animais de Doenças , Ensaios de Triagem em Larga Escala , Camundongos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition mechanism enabling the design of stable analogues.
RESUMO
One of the major barriers to successful axon regeneration in the adult CNS is the presence of inhibitory molecules that originate from the myelin sheath and glial scar. So far, only a small number of pharmacological compounds have exhibited functional activity against CNS inhibitors in promoting axon regeneration after injury. To search for novel compounds that enhance neurite outgrowth in vitro, we initiated a screen of a collection of natural products. We identified four compounds with the potential to promote growth over a myelin substrate. Of these, Amphotericin B (AmB) was shown to enhance neurite outgrowth and antagonize activities of major myelin associated inhibitors and glial-scar-derived chondroitin sulfate proteoglycans. AmB was found to activate Akt and thereby suppress the activity of glycogen synthase kinase 3 beta. Also, a cell permeable peptide that inhibits Akt activity was shown to block the effect of AmB in promoting axonal growth, while another peptide that increases Akt activity stimulated axonal growth in the presence of the myelin associated inhibitors. Our results suggest that AmB can promote neurite outgrowth over a wide range of inhibitory substrates via a mechanism that involves activation of Akt.
Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Axônios/efeitos dos fármacos , Produtos Biológicos/farmacologia , Neurônios/efeitos dos fármacos , Proteína Oncogênica v-akt/metabolismo , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Proteoglicanas de Sulfatos de Condroitina/antagonistas & inibidores , Proteoglicanas de Sulfatos de Condroitina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Glicoproteína Associada a Mielina/antagonistas & inibidores , Glicoproteína Associada a Mielina/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Neuritos/efeitos dos fármacos , Análise de Componente Principal , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
A series of benzofuran-3-one indole phosphatidylinositol-3-kinases (PI3K) inhibitors identified via HTS has been prepared. The optimized inhibitors possess single digit nanomolar activity against p110alpha (PI3K-alpha), good pharmaceutical properties, selectivity versus p110gamma (PI3K-gamma), and tunable selectivity versus the mammalian target of rapamycin (mTOR). Modeling of compounds 9 and 32 in homology models of PI3K-alpha and mTOR supports the proposed rationale for selectivity. Compounds show activity in multiple cellular proliferation assays with signaling through the PI3K pathway confirmed via phospho-Akt inhibition in PC-3 cells.
Assuntos
Benzofuranos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Benzofuranos/química , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Serina-Treonina Quinases TORRESUMO
Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Purinas/química , Pirazóis/química , Piridinas/química , Sítios de Ligação , Células CACO-2 , Linhagem Celular Tumoral , Cristalografia por Raios X , Imunoensaio de Fluorescência por Polarização , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Purinas/síntese química , Purinas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Serina-Treonina Quinases TORRESUMO
A series of (hetero)arylpyrimidines agonists of the Wnt-beta-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3beta inhibition indicating that the Wnt-beta-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated beta-catenin formation in bone.
Assuntos
Imidazóis/química , Pirimidinas/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pirimidinas/síntese química , Pirimidinas/farmacologia , Proteínas Recombinantes de Fusão/agonistas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Crânio/metabolismo , Proteínas Wnt/agonistas , Proteínas Wnt/genética , Proteína Wnt3 , Proteína Wnt3A , beta Catenina/agonistasRESUMO
This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Ligação Competitiva , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Serina-Treonina Quinases TORRESUMO
N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-microM ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13, and MMP-12. Compound 53 shows a good balance of potent ADAMTS-5 inhibition, moderate CYP3A4 inhibition and good rat liver microsome stability. This series of compounds represents progress towards selective ADAMTS-5 inhibitors as disease modifying osteoarthritis agents.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/química , Acetamidas/síntese química , Acetamidas/farmacologia , Proteínas ADAM/metabolismo , Proteína ADAMTS4 , Proteína ADAMTS5 , Animais , Química Farmacêutica/métodos , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Modelos Químicos , Osteoartrite/tratamento farmacológico , Pró-Colágeno N-Endopeptidase/metabolismo , RatosRESUMO
Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in the central nervous system (CNS). Herein we report the discovery of compound 15 (PF-06795071), a potent and selective covalent MAGL inhibitor, featuring a novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series with more lipophilic leaving groups. The design strategy focused on identifying an optimized leaving group that delivers MAGL potency, serine hydrolase selectivity, and CNS exposure while simultaneously reducing log D, improving solubility, and minimizing chemical lability. Compound 15 achieves excellent CNS exposure, extended 2-AG elevation effect in vivo, and decreased brain inflammatory markers in response to an inflammatory challenge.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Carbamatos/síntese química , Carbamatos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Monoacilglicerol Lipases/antagonistas & inibidores , Neurite (Inflamação)/tratamento farmacológico , Amidoidrolases/antagonistas & inibidores , Animais , Ácidos Araquidônicos/metabolismo , Biomarcadores , Química Encefálica/efeitos dos fármacos , Cães , Desenho de Fármacos , Descoberta de Drogas , Endocanabinoides/metabolismo , Glicerídeos/metabolismo , Humanos , Macaca mulatta , Modelos Moleculares , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC50 = 0.34 nM) and selective (N/C interaction EC50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.