RESUMEN
N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.
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Hidrolasas de Éster Carboxílico , Vía de Señalización Wnt , Fenómenos BiofísicosRESUMEN
1-Phenyl-1H-1,2,3-triazole 1 (ARUK3001185) was prepared on large scale from aniline 4 by application of both (1) a copper catalyzed azide-alkyne cycloaddition (CuAAC) with (trimethylsilyl)acetylene, and (2) a Clark modification of the Sakai reaction. The one-pot Sakai-Clark method with (MeO)2CHCH[double bond, length as m-dash]NNHTos (2b) proved to be superior as it was operationally simple, metal-free, and avoided the use of aryl azide 7. The Sakai-Clark method has been reliably performed on large scale to produce >100 g of 1 in good efficiency and high purity.
RESUMEN
The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 µM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC50 0.0067 µM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.
Asunto(s)
Cristalografía por Rayos XRESUMEN
Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer's disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets.
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Inhibidores Enzimáticos , Esterasas , Encéfalo/metabolismo , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Esterasas/metabolismo , Vía de Señalización WntRESUMEN
Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC50 < 500 nM. A critical selection process was then applied with two clusters and two singletons (1-4d) selected for hit validation. Optimization of 4d guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/ß-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-b]pyradizin-3(2H)-one series 4 represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.
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Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Esterasas/antagonistas & inhibidores , Animales , Sitios de Unión , Cristalografía por Rayos X , Ensayos Analíticos de Alto Rendimiento , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Simulación del Acoplamiento Molecular , Unión Proteica , Relación Estructura-Actividad , Vía de Señalización Wnt/efectos de los fármacos , beta Catenina/efectos de los fármacosRESUMEN
The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer's disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors.
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Butiratos/farmacología , Inhibidores Enzimáticos/farmacología , Esterasas/antagonistas & inhibidores , Ésteres/farmacología , Indoles/farmacología , Butiratos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Esterasas/metabolismo , Ésteres/química , Humanos , Indoles/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The COVID-19 pandemic has clearly brought the healthcare systems worldwide to a breaking point, along with devastating socioeconomic consequences. The SARS-CoV-2 virus, which causes the disease, uses RNA capping to evade the human immune system. Nonstructural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small-molecule inhibitors of nsp14 methyltransferase (MTase) activity, we developed and employed a radiometric MTase assay to screen a library of 161 in-house synthesized S-adenosylmethionine (SAM) competitive MTase inhibitors and SAM analogs. Among six identified screening hits, SS148 inhibited nsp14 MTase activity with an IC50 value of 70 ± 6 nM and was selective against 20 human protein lysine MTases, indicating significant differences in SAM binding sites. Interestingly, DS0464 with an IC50 value of 1.1 ± 0.2 µM showed a bisubstrate competitive inhibitor mechanism of action. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein MTases. The structure-activity relationship provided by these compounds should guide the optimization of selective bisubstrate nsp14 inhibitors and may provide a path toward a novel class of antivirals against COVID-19, and possibly other coronaviruses.
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COVID-19/genética , Exorribonucleasas/genética , Unión Proteica/genética , SARS-CoV-2/genética , Proteínas no Estructurales Virales/genética , Antivirales/farmacología , Sitios de Unión/genética , COVID-19/virología , Humanos , Metilación , Pandemias , ARN Viral/genética , SARS-CoV-2/patogenicidad , Replicación Viral/genéticaRESUMEN
The tumour suppressor APC is the most commonly mutated gene in colorectal cancer. Loss of Apc in intestinal stem cells drives the formation of adenomas in mice via increased WNT signalling1, but reduced secretion of WNT ligands increases the ability of Apc-mutant intestinal stem cells to colonize a crypt (known as fixation)2. Here we investigated how Apc-mutant cells gain a clonal advantage over wild-type counterparts to achieve fixation. We found that Apc-mutant cells are enriched for transcripts that encode several secreted WNT antagonists, with Notum being the most highly expressed. Conditioned medium from Apc-mutant cells suppressed the growth of wild-type organoids in a NOTUM-dependent manner. Furthermore, NOTUM-secreting Apc-mutant clones actively inhibited the proliferation of surrounding wild-type crypt cells and drove their differentiation, thereby outcompeting crypt cells from the niche. Genetic or pharmacological inhibition of NOTUM abrogated the ability of Apc-mutant cells to expand and form intestinal adenomas. We identify NOTUM as a key mediator during the early stages of mutation fixation that can be targeted to restore wild-type cell competitiveness and provide preventative strategies for people at a high risk of developing colorectal cancer.
Asunto(s)
Competencia Celular , Transformación Celular Neoplásica , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Esterasas/metabolismo , Genes APC , Mutación , Adenoma/genética , Adenoma/patología , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Competencia Celular/genética , Diferenciación Celular , Proliferación Celular , Transformación Celular Neoplásica/genética , Medios de Cultivo Condicionados , Progresión de la Enfermedad , Esterasas/antagonistas & inhibidores , Esterasas/genética , Femenino , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Organoides/citología , Organoides/metabolismo , Organoides/patología , Células Madre/citología , Células Madre/metabolismo , Proteínas Wnt/metabolismo , Vía de Señalización WntRESUMEN
Notum has recently been identified as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group from Wnt proteins. There are emerging reports that Notum plays a role in human disease, with published data suggesting that targeting Notum could represent a new therapeutic approach for treating cancer, osteoporosis and neurodegenerative disorders. Complementary hit-finding strategies have been applied with successful approaches that include high-throughput screening, activity-based protein profiling, screening of fragment libraries and virtual screening campaigns. Structural studies are accelerating the discovery of new inhibitors of Notum. Three fit-for-purpose examples are LP-922056, ABC99 and ARUK3001185. The application of these small-molecule inhibitors is helping to further advance an understanding of the role Notum plays in human disease.
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Inhibidores Enzimáticos/farmacología , Esterasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Inhibidores Enzimáticos/química , Esterasas/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Regulation of the Wnt signaling pathway is critically important for a number of cellular processes in both development and adult mammalian biology. This Perspective will provide a summary of current and emerging therapeutic opportunities in modulating Wnt signaling, especially through inhibition of Notum carboxylesterase activity. Notum was recently shown to act as a negative regulator of Wnt signaling through the removal of an essential palmitoleate group. Inhibition of Notum activity may represent a new approach to treat disease where aberrant Notum activity has been identified as the underlying cause. Reliable screening technologies are available to identify inhibitors of Notum, and structural studies are accelerating the discovery of new inhibitors. A selection of these hits have been optimized to give fit-for-purpose small molecule inhibitors of Notum. Three noteworthy examples are LP-922056 (26), ABC99 (27), and ARUK3001185 (28), which are complementary chemical tools for exploring the role of Notum in Wnt signaling.
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Inhibidores Enzimáticos/química , Esterasas/antagonistas & inhibidores , Vía de Señalización Wnt , Sitios de Unión , Dominio Catalítico , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Esterasas/metabolismo , Humanos , Simulación de Dinámica Molecular , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
The COVID-19 pandemic has clearly brought the healthcare systems world-wide to a breaking point along with devastating socioeconomic consequences. The SARS-CoV-2 virus which causes the disease uses RNA capping to evade the human immune system. Non-structural protein (nsp) 14 is one of the 16 nsps in SARS-CoV-2 and catalyzes the methylation of the viral RNA at N7-guanosine in the cap formation process. To discover small molecule inhibitors of nsp14 methyltransferase (MT) activity, we developed and employed a radiometric MT assay to screen a library of 161 in house synthesized S-adenosylmethionine (SAM) competitive methyltransferase inhibitors and SAM analogs. Among seven identified screening hits, SS148 inhibited nsp14 MT activity with an IC 50 value of 70 ± 6 nM and was selective against 20 human protein lysine methyltransferases indicating significant differences in SAM binding sites. Interestingly, DS0464 with IC 50 value of 1.1 ± 0.2 µM showed a bi-substrate competitive inhibitor mechanism of action. Modeling the binding of this compound to nsp14 suggests that the terminal phenyl group extends into the RNA binding site. DS0464 was also selective against 28 out of 33 RNA, DNA, and protein methyltransferases. The structure-activity relationship provided by these compounds should guide the optimization of selective bi-substrate nsp14 inhibitors and may provide a path towards a novel class of antivirals against COVID-19, and possibly other coronaviruses.
RESUMEN
Iterative screening is a process in which screening is done in batches, with each batch filled by using machine learning to select the most promising compounds from the library based on the previous results. We believe iterative screening is poised to enhance the screening process by improving hit finding while at the same time reducing the number of compounds screened. In addition, we see this process as a key enabler of next-generation high-throughput screening (HTS), which uses more complex assays that better describe the biology but demand more resource per screened compound. To demonstrate the utility of these methods, we retrospectively analyze HTS data from PubChem with a focus on machine learning-based screening strategies that can be readily implemented in practice. Our results show that over a variety of HTS experimental paradigms, an iterative screening setup that screens a total of 35% of the screening collection over as few as three iterations has a median return rate of approximately 70% of the active compounds. Increasing the portion of the library screened to 50% yields median returns of approximately 80% of actives. Using six iterations increases these return rates to 78% and 90%, respectively. The best results were achieved with machine learning models that can be run on a standard desktop. By demonstrating that the utility of iterative screening holds true even with a small number of iterations, and without requiring significant computational resources, we provide a roadmap for the practical implementation of these techniques in hit finding.
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Descubrimiento de Drogas/métodos , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento/métodos , Aprendizaje Automático , Bibliotecas de Moléculas PequeñasRESUMEN
Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7 as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7 identified oxadiazol-2-one 23dd as a preferred example with properties consistent with drug-like chemical space. Screening 23dd in a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dd demonstrated good plasma exposure and partial blood-brain barrier penetration. Significant progress was made in developing fragment hit 7 into lead 23dd (>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.
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Inhibidores Enzimáticos/química , Esterasas/antagonistas & inhibidores , Oxadiazoles/química , Administración Oral , Animales , Sitios de Unión , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Esterasas/metabolismo , Semivida , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Relación Estructura-Actividad , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, in vitro cytotoxicity, and cardiotoxicity and were addressed through structure-activity and structure-property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable in vitro activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite, which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rγnull (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action.
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Antimaláricos/química , Hemoproteínas/antagonistas & inhibidores , Imidazoles/química , Plasmodium falciparum/fisiología , Proteínas Protozoarias/antagonistas & inhibidores , Piridinas/química , Animales , Antimaláricos/metabolismo , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Modelos Animales de Enfermedad , Semivida , Hemoproteínas/metabolismo , Imidazoles/metabolismo , Imidazoles/farmacología , Imidazoles/uso terapéutico , Estadios del Ciclo de Vida/efectos de los fármacos , Malaria/tratamiento farmacológico , Malaria/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Microsomas Hepáticos/metabolismo , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Piridinas/metabolismo , Piridinas/farmacología , Piridinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
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Hidrolasas de Éster Carboxílico/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pirroles/química , Pirroles/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Hidrolasas de Éster Carboxílico/química , Evaluación Preclínica de Medicamentos , Modelos Moleculares , Conformación ProteicaRESUMEN
The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.
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Acetilesterasa/antagonistas & inhibidores , Amidas/química , Pirimidinas/química , Acetilesterasa/metabolismo , Amidas/metabolismo , Amidas/farmacología , Animales , Sitios de Unión , Permeabilidad de la Membrana Celular/efectos de los fármacos , Cristalografía por Rayos X , Perros , Semivida , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas/metabolismo , Simulación de Dinámica Molecular , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Background: The carboxylesterase Notum has been shown to act as a key negative regulator of the Wnt signalling pathway by mediating the depalmitoleoylation of Wnt proteins. LP-922056 (1) is an orally active inhibitor of Notum. We are investigating the role of Notum in modulating Wnt signalling in the central nervous system and wished to establish if 1 would serve as a peripherally restricted control. An accessible and improved synthetic route would allow 1 to become more readily available as a chemical tool to explore the fundamental biology of Notum and build target validation to underpin new drug discovery programs. Results: An improved, scalable synthesis of 1 is reported. Key modifications include: (1) the introduction of the C7-cyclopropyl group was most effectively achieved with a Suzuki-Miyaura cross-coupling reaction with MIDA-boronate 11 (5 â 6), and (2) C6 chlorination was performed with 1-chloro-1,2-benziodoxol-3-one (12) (6 â 7) as a mild and selective electrophilic chlorination agent. This 7-step route from 16 has been reliably performed on large scale to produce multigram quantities of 1 in good efficiency and high purity. Pharmacokinetic studies in mouse showed CNS penetration of 1 is very low with a brain/plasma concentration ratio of just 0.01. A small library of amides 17 were prepared from acid 1 to explore if 1 could be modified to deliver a CNS penetrant tool by capping off the acid as an amide. Although significant Notum inhibition activity could be achieved, none of these amides demonstrated the required combination of metabolic stability along with cell permeability without evidence of P-gp mediated efflux. Conclusion: Mouse pharmacokinetic studies demonstrate that 1 is unsuitable for use in models of disease where brain penetration is an essential requirement of the compound but would be an ideal peripherally restricted control. These data will contribute to the understanding of drug levels of 1 to overlay with appropriate in vivo efficacy endpoints, i.e., the PK-PD relationship. The identification of a suitable analogue of 1 (or 17) which combines Notum inhibition with CNS penetration would be a valuable chemical probe for investigating the role of Notum in disease models.
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NOTUM is a carboxylesterase that has been shown to act by mediating the O-depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in in vitro disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide 3 as binding in the palmitoleate pocket with modest inhibition activity (IC50 33 µM). Optimization of hit 3 by SAR studies guided by SBDD identified indazole 38 (IC50 0.032 µM) and isoquinoline 45 (IC50 0.085 µM) as potent inhibitors of NOTUM. The binding of 45 to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to 3. However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.
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Alzheimer's disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target ß-amyloid (Aß) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the 'Aß hypothesis', there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.