A5084858800- Protease and Inhibitor Mechanisms
- Cancer Cells and Metastasis
- 3D Printing in Biomedical Research
- Bone Metabolism and Diseases
- Quinazolinone synthesis and applications
- Computational Drug Discovery Methods
- Malaria Research and Control
- Cancer therapeutics and mechanisms
- Natural product bioactivities and synthesis
- Cancer Immunotherapy and Biomarkers
- Phenothiazines and Benzothiazines Synthesis and Activities
- HIV/AIDS drug development and treatment
- Pharmacogenetics and Drug Metabolism
- Bone health and treatments
- Periodontal Regeneration and Treatments
- Immune cells in cancer
- Platelet Disorders and Treatments
- Synthesis and biological activity
- vaccines and immunoinformatics approaches
- Neurogenesis and neuroplasticity mechanisms
- Renal and related cancers
- TGF-β signaling in diseases
- Lipid metabolism and disorders
- Biochemical and Structural Characterization
- Advanced Glycation End Products research
Georgia Institute of Technology
2019-2025
The Wallace H. Coulter Department of Biomedical Engineering
2019-2025
Novartis (United States)
2011-2023
The Ohio State University
2017-2020
California State University, Northridge
2018
Dana-Farber Cancer Institute
2015
Genomics Institute of the Novartis Research Foundation
2006-2014
University of California, San Francisco
2013
Tufts Medical Center
2013
Tufts University
2013
The synthesis, preclinical profile, and in vivo efficacy rat xenograft models of the novel selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) described as well rational design strategy employed to overcome development deficiencies first generation ALK 4 (TAE684). Compound is currently phase 1 2 clinical trials with substantial antitumor activity being observed ALK-positive cancer patients.
Abstract Despite the increasing interest in targeting stromal elements of tumor microenvironment, we still face tremendous challenges developing adequate therapeutics to modify landscape. A major obstacle this is our poor understanding phenotypic and functional heterogeneity cells tumors. Herein, perform an unbiased interrogation mesenchymal cells, delineating co-existence distinct subsets cancer-associated fibroblasts (CAFs) microenvironment murine carcinomas, each endowed with unique...
The intracellular protein HMGB1 is released from cells and acts as a damage-associated molecular pattern molecule during many diseases, including inflammatory bowel disease (IBD); however, the function of inflammation poorly understood. Here, we demonstrated that cytosolic regulates apoptosis by protecting autophagy proteins beclin 1 ATG5 calpain-mediated cleavage inflammation. Colitis in mice with an intestinal epithelial cell–specific Hmgb1 deletion patients IBD were both characterized...
Adult neurogenesis occurs in mammals and provides a mechanism for continuous neural plasticity the brain. However, little is known about molecular mechanisms regulating hippocampal progenitor cells (NPCs) whether their fate can be pharmacologically modulated to improve regeneration. Here, we report characterization of small molecule (KHS101) that selectively induces neuronal differentiation phenotype. Mechanism action studies revealed link KHS101 cell cycle exit specific binding TACC3...
Starting from a hit series GNF compound library collection and based on cell-based proliferation assay of Plasmodium falciparum, novel imidazolopiperazine scaffold was optimized. SAR for this compounds is discussed, focusing optimization cellular potency against wild-type drug resistant parasites improvement physiochemical pharmacokinetic properties. The lead in showed good potencies vitro decent oral exposure levels vivo. In berghei mouse infection model, one lowered the parasitemia level...
On the basis of initial success optimization a novel series imidazolopiperazines, second generation compounds involving changes in core piperazine ring was synthesized to improve antimalarial properties. These were carried out further potency and metabolic stability by leveraging outcome set vitro identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, profile and, as result, enhanced oral exposure vivo mice. found be more efficacious than...
The extracellular matrix (ECM) is critical for mammary ductal development and differentiation, but how fibroblasts regulate ECM remodeling remains to be elucidated. Herein, we used a mouse genetic model activate platelet derived growth factor receptor-alpha (PDGFRα) specifically in the stroma. Hyperactivation of PDGFRα stroma severely hindered pubertal morphogenesis, did not interrupt lobuloalveolar differentiation program. Increased stromal signaling induced fat pad fibrosis with...
This manuscript describes a new method for forming basal-in MCF10A organoids using commercial 384-well ultra-low attachment (ULA) microplates and the development of associated live-cell imaging automated analysis protocols. The use ULA platform makes this more broadly accessible than previously reported hanging drop systems enables in-incubator imaging. Therefore, time points can be captured on frequent basis to improve tracking early organoid formation growth. However, one major challenge...
Here we report the design and evaluation of a bifunctional, small molecule switch that induces targeted immune response against tumors in vivo. A high affinity ligand for prostate specific membrane antigen (PSMA) was conjugated to hapten binds dinitrophenyl (DNP)-specific antibodies. When introduced into hu-PBL-NOD/SCID mice previously immunized with KLH-DNP immunogen, this conjugate induced antibody-dependent cellular cytotoxicity (ADCC) PSMA-expressing tumor cells mouse xenograft model....
The contribution of the tumor microenvironment to pancreatic ductal adenocarcinoma (PDAC) development is currently unclear. We therefore examined consequences disrupting paracrine Hedgehog (HH) signaling in PDAC stroma. Herein, we show that ablation key HH gene Smoothened (Smo) stromal fibroblasts led increased proliferation cells. Furthermore, Smo deletion resulted proteasomal degradation suppressor PTEN and activation oncogenic protein kinase B (AKT) fibroblasts. An unbiased proteomic...
Vascular hypo-fibrinolysis is a historically underappreciated and understudied aspect of venous thromboembolism (VTE). This paper describes the development micro-clot dissolution assay for quantifying fibrinolytic capacity endothelial cells - key driver VTE development. enabled using aqueous two-phase systems (ATPS) to bioprint microscale fibrin clots over human umbilical vein (HUVECs). Importantly, these micro-clots are orders magnitude smaller than conventional constructs allow...
Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite yoelii (Py) as well hypnozoites simian cynomolgi (Pc). We applied these various assays to cell-based lead optimization imidazopyrazines, exemplified by 3 (KAI407), show that compounds within series with improved pharmacokinetic properties achieve causal prophylactic in vivo may have potential target dormant...
This paper describes an experimental characterization scheme of the biophysical properties reconstituted hydrogel matrices based on indentation testing, quantification transport via microfluidics, and confocal reflectance microscopy analysis. While methods for characterizing hydrogels exist are widely used, they often do not measure diffusive convective concurrently, determine relationship between microstructure properties, decouple matrix mechanics properties. Our integrated approach...
A novel family of 1H-imidazol-2-yl-pyrimidine-4,6-diamines has been identified with potent activity against the erythrocyte-stage Plasmodium falciparum (Pf), most common causative agent malaria. systematic SAR study resulted in identification compound 40 which exhibits good potency both wild-type and drug resistant parasites vivo pharmacokinetic properties.
Screening our in-house compound collection using a cell based Plasmodium falciparum proliferation assay we discovered known pan-kinase inhibitor scaffold as hit. Further optimization of this series led us to novel benzamide which was devoid human kinase activity while retaining its antiplasmodial activity. The evolution leading optimized candidates with good cellular potency against multiple strains well decent in vivo profile is described Letter.
This paper describes printing of microscale fibroblast-laden matrices using an aqueous two-phase approach that controls thrombin-mediated enzymatic crosslinking fibrin. Optimization formulations enabled polymerization consistent sub-microliter volumes cell-laden When plasminogen was added to these micro-scaffolds, the primary normal human lung fibroblasts converted it plasmin, triggering gradual degradation Time-lapse live-cell imaging and automated image analysis provided readouts time 50%...