Discovery of Reversible Inhibitors of KDM1A Efficacious in Acute Myeloid Leukemia Models.

Lysine-specific demethylase 1 (LSD1 or KDM1A) is a FAD-dependent enzyme that acts as a transcription corepressor or coactivator by regulating the methylation status of histone H3 lysines K4 and K9, respectively. KDM1A represents an attractive target for cancer therapy. While, in the past, the main medicinal chemistry strategy toward KDM1A inhibition was based on the optimization of ligands that irreversibly bind the FAD cofactor within the enzyme catalytic site, we and others have also identified reversible inhibitors. Herein we reported the discovery of 5-imidazolylthieno[3,2-b]pyrroles, a new series of KDM1A inhibitors endowed with picomolar inhibitory potency, active in cells and efficacious after oral administration in murine leukemia models.

Miocardiopatía periparto. Una rara pero peligrosa complicación obstétrica / Peripartum cardiomyopathy. A rare but dangerous obstetric complication

La miocardiopatía periparto es una patología poco frecuente que puede conllevar a una alta tasa de mortalidad por el compromiso cardiaco si no se realiza un manejo oportuno y adecuado. Debido a su presentación clínica, las similitudes con síntomas propios del embarazo y aquellos generados por la preeclampsia, se convierte en un diagnóstico de exclusión que requiere de alta sospecha clínica. Se presenta el caso clínico de una paciente de 33 años de edad con diagnóstico de preeclampsia atípica, disfunción hepática, hematológica y renal en el puerperio, quien presentó evolución car diovascular tórpida a pesar del manejo adecuado por lo cual se sospechó y objetivó el diagnóstico de miocardiopatía periparto que progresó a una falla cardiaca aguda con disfunción multiorgánica y necesidad de trasplante cardiaco. (Acta Med Colomb 2019; 44: 119-123).

Peripartum cardiomyopathy is a rare pathology that can lead to a high mortality rate due to cardiac compromise if timely and adequate management is not performed. Due to its clinical presentation, the similarities with typical symptoms of pregnancy and those generated by preeclampsia, becomes a diagnosis of exclusion that requires high clinical suspicion. The clinical case of a 33-year-old patient with a diagnosis of atypical preeclampsia, hepatic, hematological and renal dysfunction in the puerperium is presented. She had a torpid cardiovascular evolution despite adequate manage ment, which led to the diagnosis and suspicion of peripartum myocardiopathy that progressed to acute heart failure with multi-organ dysfunction and need for heart transplantation. (Acta Med Colomb 2019; 44: 119-123).

Parents as Role Models: Associations Between Parent and Young Children's Weight, Dietary Intake, and Physical Activity in a Minority Sample.

Objective We examined the association between parent and child fruit and vegetable (F&V) intake, physical activity (PA), and body mass index in an ethnic minority and low-income sample. Methods The study sample consisted of 86 children ages 5-7 years (80% Hispanic) and their parents. Three parent health variables (healthy weight, recommended F&V servings per day, and recommended weekly PA) were used to create a healthy role model index. Associations between the parent index and corresponding child health behaviors and weight were examined. Results Most parents (53.5%) were not healthy role models, 30.2% were limited healthy role models, 16.3% were good role models, and none were excellent role models; most parents and children did not meet guidelines for healthy weight, F&V intake, and PA. Parents who scored higher on the index were more likely to have children with higher levels of F&V. Furthermore, parents who had a healthy weight were 3.7 times more likely to have a child who had a healthy weight. Additionally, parents who were consuming the recommended servings of F&V per day were 10 times more likely to have children who were also consuming the recommended servings of F&V per day compared to parents who were not consuming the recommended servings of F&V per day. Conclusions for Practice These findings suggest the important role of parental modeling of healthy behaviors to their young children among minority/low-income families. Parents may serve as an important mechanism of change for children's health status by increasing their own healthy lifestyle behaviors.

Novel potent inhibitors of the histone demethylase KDM1A (LSD1), orally active in a murine promyelocitic leukemia model.

BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor. MATERIAL & METHODS: The KDM1A inhibitors 5a-w were synthesized and tested in vitro and in vivo. The biochemical potency was determined, modulation of target in cells was demonstrated on KDM1A-dependent genes and the anti-clonogenic activity was performed in murine acute promyelocytic Leukemia (APL) blasts. An in vivo efficacy experiment was conducted using an established murine promyelocytic leukemia model. RESULTS: We report a new series of tranylcypromine derivatives substituted on the cyclopropyl moiety, endowed with high potency in both biochemical and cellular assays. CONCLUSION: The most interesting derivative (5a) significantly improved survival rate after oral administration in a murine model of promyelocitic leukemia.

Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration.

Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC50, thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2.9 µM) in complex with the enzyme. Initial expansion of this chemical class, both modifying core structure and decorating benzamide moiety, was directed toward the definition of the moieties responsible for the interaction with the enzyme. Preliminary optimization led to compound 90, which inhibited the enzyme with a submicromolar IC50 (0.162 µM), capable of inhibiting the target in cells.

Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship.

The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.

Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent.

We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic.

Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A.

Epigenetics alterations including histone methylation and acetylation, and DNA methylation, are thought to play important roles in the onset and progression of cancer in numerous tumour cell lines. Lysine-specific demethylase 1 (LSD1 or KDM1A) is highly expressed in different cancer types and inhibiting KDM1A activity seems to have high therapeutic potential in cancer treatment. In the recent years, several inhibitors of KDM1A have been prepared and disclosed. The majority of these derivatives were designed based on the structure of tranylcypromine, as the cyclopropane core is responsible for the covalent interaction between the inhibitor and the catalytic domain of KDM proteins. In this study, we have further extended the SAR regarding compounds 1a-e, which were recently found to inhibit KDM1A with good activity. The decoration of the phenyl ring at the ß-position of the cyclopropane ring with small functional groups, mostly halogenated, and in particular at the meta position, led to a significant improvement of the inhibitory activity against KDM1A, as exemplified by compound 44a, which has a potency in the low nanomolar range (31 nM).

Evidence-based fitness promotion in an afterschool setting: implementation fidelity and its policy implications.

Little is known about how the adoption of evidence-based physical activity (PA) curricula by out-of-school time (OST) programs affects children's physical fitness, and there are no clear guidelines of what constitutes reasonable gains given the types of PA instruction currently offered in these programs. Using a three-wave, quasi-experimental, naturalistic observation design, this study evaluated the implementation of an evidence-based PA instruction curriculum (Sports, Play, and Active Recreation for Kids [SPARK]) and examined whether the potential health benefits of evidence-based PA instruction can be replicated in this context when compared to OST programs that do not use evidence-based PA curricula. Quality of PA instruction and SPARK implementation fidelity were also assessed. Results indicated that children in the non-evidence-based/standard PA instruction programs engaged in higher levels of moderate-to-vigorous PA (MVPA) and showed greater improvements in fitness levels over time. The findings from this chapter suggest that while it is generally accepted that evidence-based approaches yield higher levels of PA when implemented by researchers under controlled conditions, findings are inconsistent when evidence-based PA instruction is implemented in the field, under presumably less controlled conditions. It appears that when it comes to PA instruction in afterschool, either less structured activities or well-implemented evidence-based practices could be the key to promoting higher PA levels and greater health and fitness for school-aged children.

Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: a novel class of irreversible inhibitors of histone demethylase KDM1A.

Histone demethylase KDM1A (also known as LSD1) has become an attractive therapeutic target for the treatment of cancer as well as other disorders such as viral infections. We report on the synthesis of compounds derived from the expansion of tranylcypromine as a chemical scaffold for the design of novel demethylase inhibitors. These compounds, which are substituted on the cyclopropyl core moiety, were evaluated for their ability to inhibit KDM1A in vitro as well as to function in cells by modulating the expression of Gfi-1b, a well recognized KDM1A target gene. The molecules were all found to covalently inhibit KDM1A and to become increasingly selective against human monoamine oxidases MAO A and MAO B through the introduction of bulkier substituents on the cyclopropylamine ring. Structural and biochemical analysis of selected trans isomers showed that the two stereoisomers are endowed with similar inhibitory activities against KDM1A, but form different covalent adducts with the FAD co-enzyme.

Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo.

In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.

School-based health promotion intervention: parent and school staff perspectives.

BACKGROUND: The prevalence of childhood obesity is high, particularly among minority youth. The objective of this article was to evaluate parent and school staff perspectives of childhood health and weight qualitatively to guide the development of a school-based obesity prevention program for minority youth. METHODS: Hispanic parents (N = 9) of first graders participated in 1 of 3 focus groups, consisting of 3 parents each. School staff (N = 7) participated in 1 focus group. All sessions were digitally recorded and transcribed verbatim. Using NVivo, 2 independent coders rated the transcriptions to identify themes and a third coder addressed commonalities and discrepancies in the coding schemes. RESULTS: Parents and school staff have conflicting views over whose responsibility it is to provide nutritional education and participation in physical activity (PA). Parents felt the school should teach children about healthy nutrition, provide guidance in the cafeteria, and offer more structured PA in school. In contrast, school staff noted that parents have the primary responsibility of ensuring children get adequate nutrition and PA. CONCLUSIONS: Despite contrasting views, parents and staff agreed with the need for comprehensive school-based obesity prevention efforts emphasizing parent and teacher collaboration to promote healthy school and home environments.

Parent perspectives of diabetes management in schools.

PURPOSE: The purpose of this study is to investigate parent reports of the diabetes care support their children receive in school, their concerns about diabetes management in school, and their knowledge of federal laws that protect children with diabetes. In addition, the study explores ethnic and socioeconomic status differences in diabetes management in school. METHODS: An ethnically heterogeneous sample of 309 parents of children with diabetes was recruited from a community-based and a university-based diabetes outpatient clinic. Parents completed a survey assessing supports their child's school provides for diabetes care, worries about diabetes care in school, and awareness of federal laws that pertain to children with diabetes. RESULTS: Many children did not have a written care plan or a nurse at school, but significantly more white children had these supports than Hispanic or black children. Most children were not allowed to check blood glucose levels or administer insulin in class. Most parents were worried about hyperglycemia and hypoglycemia in school, and most were not at all or only a little confident in the school's ability to care for diabetes. Most parents were not aware of federal laws, but high-income and white parents were more likely to be aware. CONCLUSIONS: According to parents in the current study, children receive inadequate diabetes management support in schools. Minority children are less likely to receive supports than white children. Parents are worried about diabetes management in school, but most do not have the knowledge of federal laws necessary to protect their children.

3-Amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: a new class of CDK2 inhibitors.

We have recently reported about a new class of Aurora-A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. Here we describe the synthesis and early expansion of CDK2/cyclin A-E inhibitors belonging to the same chemical class. Synthesis of the compounds was accomplished using a solution-phase protocol amenable to rapid parallel expansion. Compounds with nanomolar activity in the biochemical assay and able to efficiently inhibit CDK2-mediated tumor cell proliferation have been obtained.

Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors.

N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC50=808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By exploiting crystal structures of several complexes between CDK2 and inhibitors and applying structure-based drug design (SBDD), we rapidly discovered a very potent and selective CDK2 inhibitor 4-[(5-isopropyl-1,3-thiazol-2-yl)amino] benzenesulfonamide (compound 4, IC50=20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.