A5057704012- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Computational Drug Discovery Methods
- Peptidase Inhibition and Analysis
- Protein Kinase Regulation and GTPase Signaling
- Bioactive Compounds and Antitumor Agents
- Cancer Mechanisms and Therapy
- Cancer-related Molecular Pathways
- RNA Interference and Gene Delivery
- Synthesis and Reactivity of Heterocycles
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- Microtubule and mitosis dynamics
- Enzyme Structure and Function
- Biochemical Acid Research Studies
- Quinazolinone synthesis and applications
- Cancer, Hypoxia, and Metabolism
- Wnt/β-catenin signaling in development and cancer
- Cellular transport and secretion
- Metabolism and Genetic Disorders
- Angiogenesis and VEGF in Cancer
- Synthesis and biological activity
- Nuclear Receptors and Signaling
- Fluorine in Organic Chemistry
- Pancreatic function and diabetes
Universidade Estadual de Campinas (UNICAMP)
2017-2024
Instituto Nacional de Metrologia, Qualidade e Tecnologia
2018
Discovery Institute
2016
Sanford Burnham Prebys Medical Discovery Institute
2008-2016
Universidade de São Paulo
2001-2006
Universidade Federal de São Carlos
2005-2006
University of British Columbia
2005
β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates signaling internalization degradation the complex. Here, using gain-of-function screen kinome, we report that AP2 associated kinase 1 (AAK1), known enhancer, inhibits signaling. Reciprocally, AAK1...
We describe SGC-GAK-1 (11), a potent, selective, and cell-active inhibitor of cyclin G-associated kinase (GAK), together with structurally related negative control SGC-GAK-1N (14). 11 was highly selective in an vitro kinome-wide screen, but cellular engagement assays defined RIPK2 as collateral target. identified 18 potent lacking GAK activity. Together, this chemical probe set can be used to interrogate biology.
Targeting parasite's protein kinase Malaria elimination goals are constantly eroded by the challenge of emerging drug and insecticide resistance. Alam et al. have taken established targets—CLK kinases involved in regulation RNA splicing—and investigated how inhibition enzymes blocks completion its complex life cycle. They identified an inhibitor CLK that was 100-fold less active against most closely related human effective at clearing rodent malaria parasites. Not only does this compound...
Abstract 4‐Anilinoquinolines were identified as potent and narrow‐spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator viral bacterial entry into host cells. Optimization 4‐anilino group 6,7‐quinoline substituents produced GAK with nanomolar activity, over 50 000‐fold selectivity relative to other members numb‐associated (NAK) subfamily, a compound (6,7‐dimethoxy‐ N ‐(3,4,5‐trimethoxyphenyl)quinolin‐4‐amine; 49 ) kinome profile. These compounds may be useful...
Thiamin pyrophosphate is an essential coenzyme in all organisms that depend on fermentation, respiration or photosynthesis to produce ATP. It synthesized through two independent biosynthetic routes: one for the synthesis of 2-methyl-4-amino-5-hydroxymethylpyrimidine (pyrimidine moiety) and another 4-methyl-5-(β-hydroxyethyl) thiazole phosphate (thiazole moiety). Herein, we will describe three-dimensional structure THI1 protein from Arabidopsis thaliana determined by single wavelength...
UBC13 is a noncanonical ubiquitin conjugating enzyme (E2) that has been implicated in variety of cellular signaling processes due to its ability catalyze formation lysine 63-linked polyubiquitin chains on various substrates. In particular, required for by receptors important immune regulation, making it candidate target inflammatory diseases. also critical double-strand DNA repair and thus potential radiosensitizer chemosensitizer oncology. The authors developed high-throughput screening...
The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes linked to variety tumors. However, understanding the role VRKs establishing their potential use as targets for therapeutic intervention has limited by lack tool compounds that can specifically modulate activity these cells. Here we identified BI-D1870, dihydropteridine inhibitor RSK kinases, promising starting point development...
We demonstrate for the first time that 4H-1,2,6-thiadiazin-4-one (TDZ) can function as a chemotype design of ATP-competitive kinase inhibitors. Using insights from co-crystal structure 3,5-bis(arylamino)-4H-1,2,6-thiadiazin-4-one bound to calcium/calmodulin-dependent protein 2 (CaMKK2), several analogues were identified with micromolar activity through targeted displacement water molecules in active site. Since TDZ showed reduced promiscuity compared their 2,4-dianilinopyrimidine counter...
Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for treatment neurodegenerative diseases, including Alzheimer's disease (AD) Down's syndrome. Recently, inhibition been investigated potential diabetes, while DYRK1A's role mediator in cell cycle garnered oncologic indications. Structure–activity relationship (SAR) analysis...
Abstract Calcium/Calmodulin-dependent Protein Kinase 2 (CAMKK2) acts as a signaling hub, receiving signals from various regulatory pathways and decoding them via phosphorylation of downstream protein kinases - such AMPK (AMP-activated kinase) CAMK types I IV. CAMKK2 relevance is highlighted by its constitutive activity being implicated in several human pathologies. However, at present, there are no selective small-molecule inhibitors available for this kinase. Moreover, closest homolog,...
<h2>Abstract</h2> Overexpression of the anti-apoptotic Bcl-2 family proteins occurs commonly in human cancers. Bfl-1 is highly expressed some types malignant cells, contributing significantly to tumor cell survival and chemoresistance. Therefore, it would be desirable have chemical antagonists Bfl-1. To this end, we devised a fluorescence polarization assay (FPA) using protein fluorescein-conjugated Bid BH3 peptide, which was employed for high-throughput screening libraries. Approximately 66...
The calcium/calmodulin-dependent protein kinases (CAMKKs) are upstream activators of CAMK1 and CAMK4 signalling have important functions in neural development, maintenance signalling, as well other aspects biology such Ca2+ the cardiovascular system. To support development specific inhibitors CAMKKs we determined crystal structure CAMKK1 with two ATP-competitive inhibitors. structures reveal small but exploitable differences between CAMKK2, despite high sequence identity, which could be used...
Selective inhibitors of DYRK1A are interest for the treatment cancer, Type 2 diabetes and neurological disorders. Optimization imidazo [1,2-b]pyridazine fragment 1 through structure-activity relationship exploration in silico drug design efforts led to discovery compound 17 as a potent cellular inhibitor with selectivity over much kinome. The binding mode was elucidated X-ray crystallography, facilitating rational 29, an improved kinase respect closely related CLK kinases.
Nuclear receptor TR3/Nur77/NR4A1 binds several antiapoptotic Bcl-2-family proteins (Bcl-B, Bcl-2, Bfl-1) in a non-BH3dependent manner.A 9-amino-acid peptide derived from full-length TR3 with polyarginine tail (TR3-r8) recapitulates TR3's binding specificity, displaying high affinity for Bcl-B.TR3-r8 was used to screen small molecule Bcl-B inhibitors.A fluorescence polarization assay (FPA) employing fluorescein isothiocyanate (FITC)-labeled TR3-r8 (FITC-TR3-r8) and protein optimized,...
To investigate the biocompatibility, osteogenic bioactivity and mRNA expression of osteo/odontogenic markers bone morphogenetic protein 2 (BMP-2), osteocalcin (OC) alkaline phosphatase (ALP), induced by heparin in human dental pulp cells (hDPCs).hDPCs were exposed to heparin, cell viability was assessed 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT), death evaluated flow cytometry. Osteogenic (ALP) assay, detection calcium deposits alizarin red staining (ARS). The gene BMP-2,...
Abstract We describe SGC-GAK-1 ( 11 ), a potent, selective, and cell-active inhibitor of cyclin G associated kinase (GAK), together with structurally-related negative control SGC-GAK-1N 14 ). is highly selective in kinome-wide screen, but cellular engagement assays defined RIPK2 as collateral target. identified 18 potent lacking GAK activity. Together, the chemical probe set 11, , can be used to interrogate biology inhibition.
ABSTRACT The human genome encodes two active Vaccinia-related protein kinases (VRK), VRK1 and VRK2. These proteins have been implicated in a number of cellular processes linked to variety tumors. However, understanding the role VRKs establishing their potential use as targets for therapeutic intervention has limited by lack tool compounds that can specifically modulate activity these cells. Here we identified BI-D1870, dihydropteridine inhibitor RSK kinases, promising starting point...
The dual-specificity protein kinase MKK3 has been implicated in tumor cell proliferation and survival, yet its precise role cancer remains inconclusive. A critical step elucidating the kinase's involvement disease biology is identification of potent, cell-permeable inhibitors. Presently, lacks a dedicated tool compound for these purposes, along with validated methods facile screening, identification, optimization In this study, we have developed TR-FRET-based enzymatic assay detection...
Selective inhibitors of DYRK1A are interest for the treatment cancer, Type 2 diabetes and neurological disorders. Optimization imidazo[1,2-b]pyridazine fragment 1 through structure−activity relationship exploration in silico drug design efforts led to discovery compound 17 as a potent cellular inhibitor with selectivity over much kinome. The binding mode was elucidated X-ray crystallography, facilitating rational 29, an improved kinase respect closely related CLK kinases.
Phosphoglucose isomerase (PGI) is the second enzyme in glycolytic pathway and catalyzes an aldose–ketose isomerization. Outside cell, PGI has been found to function as both a cytokine growth factor. The human pgi gene was cloned expressed purified homogeneity. Isomorphous crystals were obtained under two conditions belong P212121 space group, with unit-cell parameters = 80.37, b 107.54, c 270.33 Å. A 94.7% complete data set processed limiting resolution of 2.6 asymmetric unit contains hPGI...