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Deep learning-driven scaffold hopping in the discovery of Akt kinase inhibitors.

Chem Commun (Camb) 2021 Sep 24. Epub 2021 Sep 24.

College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.

Scaffold hopping has been widely used in drug discovery and is a topic of high interest. Here a deep conditional transformer neural network, SyntaLinker, was applied for the scaffold hopping of a phase III clinical Akt inhibitor, AZD5363. A number of novel scaffolds were generated and compound 1a as a proof-of-concept was synthesized and validated by biochemical assay. Read More

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September 2021

Time of Flight in Perspective: Instrumental and Computational Aspects of Time Resolution in Positron Emission Tomography.

IEEE Trans Radiat Plasma Med Sci 2021 Sep 27;5(5):598-618. Epub 2021 May 27.

Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104 USA.

The first time-of-flight positron emission tomography (TOF-PET) scanners were developed as early as in the 1980s. However, the poor light output and low detection efficiency of TOF-capable detectors available at the time limited any gain in image quality achieved with these TOF-PET scanners over the traditional non-TOF PET scanners. The discovery of LSO and other Lu-based scintillators revived interest in TOF-PET and led to the development of a second generation of scanners with high sensitivity and spatial resolution in the mid-2000s. Read More

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September 2021

Improving the Flow: Optimization of Available Triage Standing Medication Orders in the Pediatric Emergency Department.

Pediatr Emerg Care 2021 Sep 7. Epub 2021 Sep 7.

From the Department of Pharmacy, Saint Barnabas Medical Center, Livingston Ernest Mario School of Pharmacy at Rutgers, Piscataway Department of Emergency Medicine, Saint Barnabas Medical Center, Livingston, NJ.

Background: Emergency department (ED) overcrowding has led to longer waits for patients to be seen, treated, and released. This has been coupled with an increased number of patients who leave without ever being seen by an ED provider. Improving patient throughput and decreasing ED patient length of stay while continuing to provide high-quality care is of paramount importance. Read More

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September 2021

Pharmacoprint: A Combination of a Pharmacophore Fingerprint and Artificial Intelligence as a Tool for Computer-Aided Drug Design.

J Chem Inf Model 2021 Sep 21. Epub 2021 Sep 21.

Maj Institute of Pharmacology Polish Academy of Sciences, Smetna 12 Street, 31-343, Cracow, Poland.

Structural fingerprints and pharmacophore modeling are methodologies that have been used for at least 2 decades in various fields of cheminformatics, from similarity searching to machine learning (ML). Advances in techniques consequently led to combining both these methodologies into a new approach known as the pharmacophore fingerprint. Herein, we propose a high-resolution, pharmacophore fingerprint called Pharmacoprint that encodes the presence, types, and relationships between pharmacophore features of a molecule. Read More

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September 2021

Response surface approach to optimize the removal of the critical raw material dysprosium from water through living seaweeds.

J Environ Manage 2021 Sep 17;300:113697. Epub 2021 Sep 17.

LAQV-REQUIMTE - Associated Laboratory for Green Chemistry, University of Aveiro, Aveiro, Portugal.

Dysprosium (Dy) is a rare earth element with a high economic and strategic value, and simultaneously an emerging contaminant, whose removal from wastewaters is gaining increasing attention. In this work, the Response Surface Methodology (RSM) combined with a Box-Behnken Design (3 factors-3 levels) was used to optimize the key operational conditions that influence the uptake of Dy by two living seaweed, Ulva sp. and Gracilaria sp. Read More

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September 2021

Discovery and Preclinical Pharmacology of an Oral Bromodomain and Extra-Terminal (BET) Inhibitor Using Scaffold-Hopping and Structure-Guided Drug Design.

J Med Chem 2021 Sep 20. Epub 2021 Sep 20.

Research and Development, Bristol Myers Squibb Company, P. O. Box 4000, Princeton, New Jersey 08543-4000, United States.

Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit , a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of (BMS-986158) with excellent potency in binding and functional assays. Read More

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September 2021

Discovery of AS-1763: A Potent, Selective, Noncovalent, and Orally Available Inhibitor of Bruton's Tyrosine Kinase.

J Med Chem 2021 Sep 16. Epub 2021 Sep 16.

Research and Development, Carna Biosciences, Inc., 3F BMA, 1-5-5 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.

Although Bruton's tyrosine kinase (BTK) has been recognized as a validated drug target for the treatment of B-cell malignances, the emergence of clinical resistance to the first-generation covalent BTK inhibitors is becoming a serious concern. As a part of our effort to develop noncovalent BTK inhibitors, a series of novel pyrrolopyrimidines was identified as noncovalent inhibitors of both the wild-type and C481S mutant BTKs. Subsequent lead optimization led to the identification of an orally available, potent, and selective BTK inhibitor (AS-1763) as a next-generation noncovalent BTK inhibitor. Read More

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September 2021

Diagnosis and Individualized Treatment of Three Primary Malignant Tumors: A Case Report.

Breast Cancer (Dove Med Press) 2021 9;13:519-527. Epub 2021 Sep 9.

Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.

Continuous optimization of diagnosis and treatment of malignant tumors has led to significantly prolonged survival in cancer patients. Despite the recent increase in the incidence of multiple primary malignant tumors (MPMT), it remains rare in clinical practice; therefore, normative guidance on its etiology, diagnosis, and treatment is insufficient. Here we describe the case of a patient with three primary malignant tumors, namely breast cancer, diffuse astrocytoma, and hepatic malignant perivascular epithelioid cell tumors (PEComa) and discuss relevant literature. Read More

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September 2021

Integrating Palliative Care Into a Neurosurgical Intensive Care Unit (NS-ICU): A Quality Improvement (QI) Project.

Am J Hosp Palliat Care 2021 Sep 15:10499091211045616. Epub 2021 Sep 15.

Anaesthesiology, Intensive Care and Pain Medicine Department, Tan Tock Seng Hospital, Singapore, Singapore.

Objectives: We conducted a pilot quality improvement (QI) project with the aim of improving accessibility of palliative care to critically ill neurosurgical patients.

Methods: The QI project was conducted in the neurosurgical intensive care unit (NS-ICU). Prior to the QI project, referral rates to palliative care were low. Read More

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September 2021

Toward the sustainable use of mineral phosphorus fertilizers for crop production in China: From primary resource demand to final agricultural use.

Sci Total Environ 2021 Sep 9;804:150183. Epub 2021 Sep 9.

National Academy of Agriculture Green Development, Department of Plant Nutrition, Key Laboratory of Plant-Soil Interactions, Ministry of Education, China Agricultural University, Beijing 100193, China.

Sustainable phosphorus (P) management is crucial to both food security and environmental conservation. The optimization of P input from mineral fertilizers has been advocated as an effective approach to improve P use efficiency. However, strategies for maximizing P use efficiency by linking soil-crop systems and fertilizer types with the P flow, from a whole P supply chain perspective, are lacking. Read More

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September 2021

Scaffold Hopping to Imidazo[1,2-]pyrazin-8-one Positive Allosteric Modulators of Metabotropic Glutamate 2 Receptor.

ACS Omega 2021 Sep 25;6(35):22997-23006. Epub 2021 Aug 25.

Discovery Chemistry, Discovery Sciences, Janssen Research & Development, Division of Janssen-Cilag S.A., Jarama 75A, Toledo 45007, Spain.

Glutamate hyperfunction is implicated in multiple neurological and psychiatric diseases. Activation of the mGlu2 receptor results in reduced glutamate release and decreased excitability representing a promising novel therapeutic agent for the treatment of disorders such as epilepsy, schizophrenia, mood, anxiety, and other neuropsychiatric disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs from different chemical series. Read More

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September 2021

Optimization of the Formulation of Rice Biscuits Supplemented with (L.) Powder Using Response Surface Methodology.

Int J Food Sci 2021 31;2021:5215367. Epub 2021 Aug 31.

Africa Rice Center (AfricaRice), M'be Research Station, P.O. Box 2551, Bouake, Ivory Coast, South Africa.

Trends in the food industry are nowadays directed towards the reduction of the level of trans fatty acids in food intended for human consumption. The present study was designed and aimed at valorizing (L.) powder as a substitute for margarine in the production of functional rice biscuits. Read More

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Elucidating exercise-induced skeletal muscle signaling pathways and applying relevant findings to preemptive therapy for lifestyle-related diseases.

Endocr J 2021 Sep 11. Epub 2021 Sep 11.

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

While it is well recognized that exercise represents a radical preventive and therapeutic measure for lifestyle-related diseases, it is clear that contemporary lifestyles abound with situations where exercise may be found difficult to implement on a continuous basis. Indeed, this has led to global expectations for elucidation of the exercise-activated skeletal muscle signaling pathways as well as for development of exercise mimics that effectively activate such pathways. It is shown that exercise activates the transcriptional coactivator PGC-1α via AMPK/SIRT1 in muscle, thereby not only enhancing mitochondrial function and muscle endurance but upregulating energy metabolism. Read More

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September 2021

Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode.

J Med Chem 2021 Sep 11;64(18):13780-13792. Epub 2021 Sep 11.

Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage SG1 2NY, U.K.

Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound . Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound (GSK215) that had a low predicted daily dose (45 mg, b. Read More

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September 2021

Benzothiophene derivatives as selective estrogen receptor covalent antagonists: Design, synthesis and anti-ERα activities.

Bioorg Med Chem 2021 Sep 6;47:116395. Epub 2021 Sep 6.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Estrogen receptor α emerged as a well validated therapeutic target of breast cancer for decades. However, approximately 50% of patients who initially responding to standard-of-care (SoC), such as undergo therapy of Tamoxifen, generally inevitably progress to an endocrine-resistance ER+ phenotype. Recently, selective estrogen receptor covalent antagonists (SERCAs) targeted to ERα have been demonstrated as a therapeutic alternative. Read More

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September 2021

Enabling development, manufacturing, and regulatory approval of biotherapeutics through advances in mass spectrometry.

Curr Opin Biotechnol 2021 Sep 8;71:206-215. Epub 2021 Sep 8.

Attribute Sciences, Process Development, Amgen Inc., 1 Amgen Center Drive, Thousand Oaks, CA 91320, United States. Electronic address:

Rapid technological advances have significantly improved the capability, versatility, and robustness of mass spectrometers which has led to them playing a central role in the development, characterization, and regulatory filings of biopharmaceuticals. Their application spans the entire continuum of drug development, starting with discovery research through product development, characterization, and marketing authorization and continues well into product life cycle management. The scope of application extends beyond traditional protein characterization and includes elements like clone selection, cell culture physiology and bioprocess optimization, investigation support, and process analytical technology. Read More

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September 2021

Emerging deep learning techniques using magnetic resonance imaging data applied in multiple sclerosis and clinical isolated syndrome patients (Review).

Exp Ther Med 2021 Oct 9;22(4):1149. Epub 2021 Aug 9.

Computational BioMedicine Laboratory, Institute of Computer Science, Foundation for Research and Technology-Hellas, 70013 Heraklion, Greece.

Computer-aided diagnosis systems aim to assist clinicians in the early identification of abnormal signs in order to optimize the interpretation of medical images and increase diagnostic precision. Multiple sclerosis (MS) and clinically isolated syndrome (CIS) are chronic inflammatory, demyelinating diseases affecting the central nervous system. Recent advances in deep learning (DL) techniques have led to novel computational paradigms in MS and CIS imaging designed for automatic segmentation and detection of areas of interest and automatic classification of anatomic structures, as well as optimization of neuroimaging protocols. Read More

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October 2021

Design and Evaluation of New Quinazolin-4(3)-one Derived PqsR Antagonists as Quorum Sensing Quenchers in .

ACS Infect Dis 2021 09 17;7(9):2666-2685. Epub 2021 Aug 17.

School of Life Sciences, University of Nottingham Biodiscovery Institute, University of Nottingham, Nottingham, NG7 2RD, U.K.

(PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is a pressing demand for the development of novel antimicrobial interventions. The potential use of antivirulence therapeutics to tackle bacterial infections has attracted considerable attention over the past decades as they hamper the pathogenicity of target microbes with reduced selective pressure, minimizing the emergence of resistance. Read More

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September 2021

An Optimized Self-Compensated Solution for Temperature and Strain Cross-Sensitivity in FBG Interrogators Based on Edge Filter.

Sensors (Basel) 2021 Aug 30;21(17). Epub 2021 Aug 30.

Telecommunications Laboratory LABTEL, Electrical Engineering Department, Federal University of Espírito Santo, Vitória 29075-910, Brazil.

Optical fiber sensors based on fiber Bragg gratings (FBGs) are prone to measurement errors if the cross-sensitivity between temperature and strain is not properly considered. This paper describes a self-compensated technique for canceling the undesired influence of temperature in strain measurement. An edge-filter-based interrogator is proposed and the central peaks of two FBGs (sensor and reference) are matched with the positive and negative slopes of a Fabry-Perot interferometer that acts as an optical filter. Read More

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Automatic Identification of Analogue Series from Large Compound Data Sets: Methods and Applications.

Molecules 2021 Aug 31;26(17). Epub 2021 Aug 31.

Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich Wilhelms-Universität, Friedrich-Hirzebruch-Allee 5-6, 53115 Bonn, Germany.

Analogue series play a key role in drug discovery. They arise naturally in lead optimization efforts where analogues are explored based on one or a few core structures. However, it is much harder to accurately identify and extract pairs or series of analogue molecules in large compound databases with no predefined core structures. Read More

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The Effect of Core Replacement on S64315, a Selective MCL-1 Inhibitor, and Its Analogues.

ACS Omega 2021 Aug 18;6(34):22073-22102. Epub 2021 Aug 18.

Servier Research Institute of Medicinal Chemistry, Záhony u. 7., H-1031 Budapest, Hungary.

Following the identification of thieno[2,3-]pyrimidine-based selective and potent inhibitors of MCL-1, we explored the effect of core swapping at different levels of advancement. During hit-to-lead optimization, X-ray-guided S-N replacement in the core provided a new vector, whose exploration led to the opening of the so-called deep-S2 pocket of MCL-1. Unfortunately, the occupation of this region led to a plateau in affinity and had to be abandoned. Read More

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Equal mixing time enables scale-down and optimization of a CHO cell culture process using a shaken microbioreactor system.

Biotechnol J 2021 Sep 7:e2100360. Epub 2021 Sep 7.

The Advanced Centre for Biochemical Engineering, Department of Biochemical Engineering, University College London, Gordon Street, London, WC1E 6BT, UK.

The advancement of microbioreactor technology in recent years has transformed early- and mid-stage process development. The monitoring and control capabilities of microbioreactors not only promote the quick accumulation of process knowledge but has also led to an increased scalability when compared to traditionally used systems such as shake flasks and microtitre plates. This study seeks to establish a framework for the micro-Matrix microbioreactor (Applikon-Biotechnology BV) as process development tool. Read More

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September 2021

Panel Optimization for High-Dimensional Immunophenotyping Assays Using Full-Spectrum Flow Cytometry.

Curr Protoc 2021 Sep;1(9):e222

Malaghan Institute of Medical Research, Wellington, New Zealand.

Technological advancements in fluorescence flow cytometry and an ever-expanding understanding of the complexity of the immune system have led to the development of large flow cytometry panels reaching up to 43 colors at the single-cell level. However, as panel size and complexity increase, so too does the detail involved in designing and optimizing successful high-quality panels fit for downstream high-dimensional data analysis. In contrast to conventional flow cytometers, full-spectrum flow cytometers measure the entire emission spectrum of each fluorophore across all lasers. Read More

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September 2021

Effective Organs-at-Risk Dose Sparing in Volumetric Modulated Arc Therapy Using a Half-Beam Technique in Whole Pelvic Irradiation.

Front Oncol 2021 18;11:611469. Epub 2021 Aug 18.

Department of Radiation Oncology, Ajou University School of Medicine, Suwon, South Korea.

Background: Although there are some controversies regarding whole pelvic radiation therapy (WPRT) due to its gastrointestinal and hematologic toxicities, it is considered for patients with gynecological, rectal, and prostate cancer. To effectively spare organs-at-risk (OAR) doses using multi-leaf collimator (MLC)'s optimal segments, potential dosimetric benefits in volumetric modulated arc therapy (VMAT) using a half-beam technique (HF) were investigated for WPRT.

Methods: While the size of a fully opened field (FF) was decided to entirely include a planning target volume in all beam's eye view across arc angles, the HF was designed to use half the FF from the isocenter for dose optimization. Read More

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Restarting elective endoscopy safely amidst an evolving pandemic and the impact of patient perception.

BMC Gastroenterol 2021 Sep 6;21(1):344. Epub 2021 Sep 6.

Division of Gastroenterology and Hepatology, University of Texas Medical Branch, Galveston, TX, USA.

Background: The COVID-19 pandemic has led to disruptions in elective and outpatient procedures. Guidance from the Centers for Medicare and Medicaid Services provided a framework for gradual reopening of outpatient clinical operations. As the infrastructure to restart endoscopy has been more clearly described, patient concerns regarding viral transmission during the procedure have been identified. Read More

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September 2021

Understanding ion-induced assembly of cellulose nanofibrillar gels through shear-free mixing and scanning-SAXS.

Nanoscale Adv 2021 Aug 19;3(17):4940-4951. Epub 2021 Jul 19.

Department of Chemistry, Stony Brook University Stony Brook New York 11794-3400 USA

During the past decade, cellulose nanofibrils (CNFs) have shown tremendous potential as a building block to fabricate new advanced materials that are both biocompatible and biodegradable. The excellent mechanical properties of the individual CNF can be transferred to macroscale fibers through careful control in hydrodynamic alignment and assembly processes. The optimization of such processes relies on the understanding of nanofibril dynamics during the process, which in turn requires characterization. Read More

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Estimation of the post-mortem interval: Effect of storage conditions on the determination of vitreous humour [K].

Sci Justice 2021 Sep 27;61(5):597-602. Epub 2021 Jul 27.

Department of Forensic Sciences, Pathology, Gynecology and Obstetrics, Pediatrics, University of Santiago de Compostela, Spain; Department of Statistics, Mathematical Analysis and Optimization, University of Santiago de Compostela, Spain. Electronic address:

Obtaining a reliable estimate of the post-mortem interval (PMI) has been a long-running challenge in forensic medicine. Several more or less successful techniques for making such estimates have been developed, but in recent years important advances have been made thanks to the detailed study of the relationship between the PMI and the analytes - in particular K - of the vitreous humour (VH). The extraction and pre-treatment of VH samples has been standardized, the influence of certain environmental factors on analytical results has been quantified, and some of the circumstances under which techniques become unreliable have been identified. Read More

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September 2021

Optoacoustically induced auditory brainstem responses in the mouse model enhanced through an absorbing film.

J Biomed Opt 2021 Sep;26(9)

Univ. des Saarlandes, Germany.

Significance: Optoacoustic stimulation offers an alternative stimulation strategy for the hearing organ. To serve as the base for a novel auditory prosthesis, the optoacoustic stimulation must be biocompatible and energy-saving.

Aim: Enhancing the efficiency of optoacoustic stimulation while reducing the energy input in a suited animal model. Read More

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September 2021

Heterogeneous modulation of Bcl-2 family members and drug efflux mediate MCL-1 inhibitor resistance in multiple myeloma.

Blood Adv 2021 Sep 3. Epub 2021 Sep 3.

Wilhelminen Cancer Research Institute, Vienna, Austria.

Anti-apoptotic Bcl-2 family members recently (re)emerged as key drug targets in cancer, with a tissue and tumour specific activity profile of available BH3 mimetics. In multiple myeloma, MCL-1 was described as a major gatekeeper of apoptosis. This discovery has led to the rapid establishment of clinical trials evaluating the impact of various MCL-1 inhibitors. Read More

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September 2021

Discovery of a Potent Dual SLK/STK10 Inhibitor Based on a Maleimide Scaffold.

J Med Chem 2021 Sep 31;64(18):13259-13278. Epub 2021 Aug 31.

Structural Genomics Consortium, University of Campinas (UNICAMP), Av. Dr. André Tosello, 550, Barão Geraldo, Campinas, SP 13083-886, Brazil.

SLK (STE20-like kinase) and STK10 (serine/threonine kinase 10) are closely related kinases whose enzymatic activity is linked to the regulation of ezrin, radixin, and moesin function and to the regulation of lymphocyte migration and the cell cycle. We identified a series of 3-anilino-4-arylmaleimides as dual inhibitors of SLK and STK10 with good kinome-wide selectivity. Optimization of this series led to multiple SLK/STK10 inhibitors with nanomolar potency. Read More

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September 2021