A5019003264- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Cancer Mechanisms and Therapy
- Cancer-related Molecular Pathways
- Computational Drug Discovery Methods
- Advanced Breast Cancer Therapies
- Phenothiazines and Benzothiazines Synthesis and Activities
- Malaria Research and Control
- Phytase and its Applications
- Synthesis and biological activity
- Protein Hydrolysis and Bioactive Peptides
- Research on Leishmaniasis Studies
- Chemical Synthesis and Analysis
- Ubiquitin and proteasome pathways
- Synthesis and Catalytic Reactions
- HIV/AIDS drug development and treatment
- PI3K/AKT/mTOR signaling in cancer
- Catalytic C–H Functionalization Methods
- Protein Degradation and Inhibitors
- Lung Cancer Treatments and Mutations
- Oxidative Organic Chemistry Reactions
- Microbial Metabolism and Applications
- HER2/EGFR in Cancer Research
- Colorectal Cancer Treatments and Studies
- Click Chemistry and Applications
Moffitt Cancer Center
2019-2024
University of South Florida
2008-2023
Scripps Research Institute
2018-2019
Scripps (United States)
2017
Scripps Institution of Oceanography
2017
Since the 1940s endochin and analogues thereof were known to be causal prophylactic potent erythrocytic stage agents in avian models. Preliminary screening a current vitro assay identified several 4(1H)-quinolones with nanomolar EC50 against stages of multidrug resistant W2 TM90-C2B isolates Plasmodium falciparum. Follow-up structure−activity relationship (SAR) studies on 4(1H)-quinolone key features for biological activity. Nevertheless, structure−property (SPR) conducted parallel revealed...
The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response progression-free survival in clinical trials B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a incidence adverse events has led to frequent discontinuations, limiting the development these inhibitors. By contrast, dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows but an improved safety...
A clean arylation protocol of ethyl acetoacetate was developed using hypervalent diaryliodonium salts under mild and metal-free conditions. The scope the reaction, symmetric unsymmetric iodonium with varying sterics electronics, examined. Further, this method has been applied for synthesis antimalarial compound ELQ-300, which is currently in preclinical development.
Abstract RNA splicing, the process of intron removal from pre-mRNA, is a fundamental step in gene expression regulation mediated by spliceosome. In Ewing’s sarcoma, driven EWS-FLI1 fusion transcription factor, splicing essential for generating in-frame transcripts. Cyclin-dependent kinase 11 (CDK11) has been identified as bona fide responsible phosphorylating SF3B1, core component U2 snRNP. Both CDK11 and SF3B1 are crucial pre-mRNA maturation, with inhibition either impairing disrupting...
The continued proliferation of malaria throughout temperate and tropical regions the world has promoted a push for more efficacious treatments to combat disease. Unfortunately, recent remedies such as artemisinin combination therapies have been rendered less effective due developing parasite resistance, new drugs are required that target in liver support disease elimination efforts. Research was initiated revisit antimalarials developed 1940s 1960s were deemed unsuitable use therapeutic...
Malaria deaths have been decreasing over the last 10–15 years, with global mortality rates having fallen by 47% since 2000. While World Health Organization (WHO) recommends use of artemisinin-based combination therapies (ACTs) to combat malaria, emergence artemisinin resistant strains underscores need develop new antimalarial drugs. Recent in vivo efficacy improvements historical ICI 56,780 reported, however, poor solubility and rapid development resistance, this compound requires further...
Photoreactive fragment-like probes have been applied to discover target proteins that constitute novel cellular vulnerabilities and identify viable chemical hits for drug discovery. Through forming covalent bonds, functionalized can achieve stronger engagement require less effort on-target mechanism validation. However, the design of probe libraries, which directly affects biological space is interrogated, effective prioritization remain critical challenges such a proteomic platform. In this...
With the exception of primaquine, tafenoquine, and atovaquone, there are very few antimalarials that target liver stage parasites. In this study, a transgenic Plasmodium berghei parasite (1052Cl1; PbGFP-Luc(con)) expresses luciferase was used to assess anti-liver activity ICI 56,780, 7-(2-phenoxyethoxy)-4(1H)-quinolone (PEQ), as well two 3-phenyl-4(1H)-quinolones (P4Q), P4Q-146 P4Q-158, by using bioluminescent imaging (BLI). Results showed all compounds were active against parasites;...
Infectious diseases are the second leading cause of deaths in world with malaria being responsible for approximately same amount as cancer 2012. Despite success prevention and control measures decreasing disease mortality rate by 45% since 2000, development single-dose therapeutics radical cure potential is required to completely eradicate this deadly condition. Targeting multiple stages parasite becoming a primary requirement new candidates antimalarial drug discovery development. Recently,...
Abstract In this Opinion article, we confront the role of artificial intelligence (AI) in targeting and understanding resistance to targeted therapy using most frequently mutated oncoprotein family human cancer, rat sarcoma virus guanosine triphosphate hydrolases (RAS GTPases), here Kirsten RAS (KRAS), as an example. Aberrant regulation active GTP-bound state KRAS is associated with tumourigenesis, aggressive disease, poor prognosis. mutations (eg, G12C, G12D, G12V, G13D, inter al.) are...
Kinetic target-guided synthesis (KTGS) is a powerful screening approach that enables identification of small molecule modulators for biomolecules. While many KTGS variants have emerged, majority the examples suffer from limited throughput and poor signal/noise ratio, hampering reliable hit detection. Herein, we present our optimized multifragment strategy tackles these limitations. This utilizes selected reaction monitoring liquid chromatography tandem mass spectrometry detection, enabling...
Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues display significantly improved solubility enhanced bioavailability, restoring key requirements typical for drug candidate profiles. The completely independent biotransformations...
Although gemcitabine is the cornerstone of care for pancreatic ductal adenocarcinoma (PDA), patients lack durable responses and relapse inevitable. While underlying mechanisms leading to resistance are likely be multifactorial, there a strong association between activating metabolism pathways clinical outcome. This study evaluated casein kinase 1 delta (CK1δ) as potential therapeutic target PDA bladder cancer, in which CK1δ frequently overexpressed. We assessed antitumor effects genetically...
The Resonance Ultrasonic Vibrations (RUV) technique was developed for in-line non-destructive crack detection in full-size silicon wafers and solar cells. RUV methodology relies on deviation of the resonance frequency response curve measured a wafer with peripheral or bulk millimeter-length identical non-cracked wafers. Three criteria were identified: (1) shift peak position; (2) increase bandwidth, (3) reduction amplitude. It observed that statistical variations parameters similarly...
Antimalarial compounds ELQ‐300 and P4Q‐391 are highly potent against the blood liver stages of Plasmodium parasite also possess transmission‐blocking activity. Gram amounts these two were required for extensive assessment in vivo efficacy, pharmacokinetics, safety. Several deficiencies existed original synthetic routes including reliance on toxic heavy‐metal reagents, harsh reaction conditions, several low‐yielding steps. Herein, we report development alternative syntheses, which reliable,...
Multiple myeloma remains an incurable malignancy due to acquisition of intrinsic programs that drive therapy resistance. Here we report casein kinase-1δ (CK1δ) and CK1ε are therapeutic targets in multiple necessary sustain mitochondrial metabolism. Specifically, the dual CK1δ/CK1ε inhibitor SR-3029 had potent vivo ex anti-multiple activity, including against primary patient specimens. RNA sequencing (RNA-seq) metabolic analyses revealed inhibiting disables metabolism by suppressing genes...
Inhibition of cyclin-dependent kinases (CDKs) has evolved as an emerging anticancer strategy. In addition to the cell cycle-regulating CDKs, transcriptional Cdk12 and Cdk13 have become focus interest they mediate a variety functions, including transition from transcription initiation elongation termination, precursor mRNA splicing, intronic polyadenylation. Here, we determine crystal structure small molecular inhibitor SR-4835 bound Cdk12/cyclin K complex at 2.68 Å resolution. The compound's...
Abstract Ewing (ES) and clear cell (CCS) sarcomas are bone soft tissue malignances in advanced relapsed disease overall survival rates remain dismal. For metastatic ES, five-year between 15% 30%. In CCS, the 30% 67%. Accordingly, there is a critical need for development of novel targeted therapeutics treatment these rare cancers. Both cancers driven by fusion proteins; EWS-FLI1 ES EWS-ATF1 which arise from separate chromosomal translocations: t(11;22)(q24;q12) t(12;22)(q13;q12) respectively....
De novo design of molecular glues transforming CDK12 inhibitors, including dinaciclib, into cyclin K degraders.