Karen L. White
A5054827010- Malaria Research and Control
- Research on Leishmaniasis Studies
- Trypanosoma species research and implications
- HIV/AIDS drug development and treatment
- Synthesis and Biological Evaluation
- Biochemical and Molecular Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Retinal Development and Disorders
- Retinal Diseases and Treatments
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- Pneumocystis jirovecii pneumonia detection and treatment
- X-ray Diffraction in Crystallography
- Quinazolinone synthesis and applications
- Crystallization and Solubility Studies
- Parasites and Host Interactions
- Synthesis and biological activity
- Immunotherapy and Immune Responses
- Epigenetics and DNA Methylation
- Synthesis and Catalytic Reactions
- Cancer Genomics and Diagnostics
- Genomics and Chromatin Dynamics
- Microencapsulation and Drying Processes
- Receptor Mechanisms and Signaling
- Cancer-related gene regulation
Monash University
2013-2023
Women's and Children's Health Network
2023
Flinders Medical Centre
2023
Johns Hopkins University
2022
Australian Regenerative Medicine Institute
2020-2021
University of Utah
2008-2017
Barwon Health
2014-2016
Huntsville Hospital
2014
Centre for Drug Research and Development
2009-2014
Mayo Clinic in Arizona
2010
Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide single-dose oral cure in humans. has successfully completed Phase I clinical trials, where it was shown be safe at doses up 1,600 mg and currently undergoing IIa trials malaria patients. Herein, we describe the discovery of exceptional pharmacokinetic properties that led its selection as development candidate. In vitro, fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC 50...
The antimalarial drug DSM265 displays activity against blood and liver stages of Plasmodium falciparum has a long predicted half-life in humans.
ELQ-300, an investigational drug for treating and preventing malaria, shows potent transmission-blocking activity in rodent models of malaria.
Drug therapy is the mainstay of antimalarial therapy, yet current drugs are threatened by development resistance. In an effort to identify new potential antimalarials, we have undertaken a lead optimization program around our previously identified triazolopyrimidine-based series Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors. The X-ray structure PfDHODH was used inform medicinal chemistry allowing identification potent and selective inhibitor (DSM265) that acts...
Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, clinical efficacy which have been compromised by resistance arising through mutations at various sites on enzyme. Here, we describe use cocrystal structures with inhibitors substrates, along pharmacokinetic profiling for design, characterization, preclinical development a selective, highly efficacious, orally available drug candidate that potently inhibits both...
MMV390048, a member of new class inhibitors the Plasmodium phosphatidylinositol 4-kinase, shows potential for both treatment and prophylaxis.
Plasmodium falciparum causes 1−2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity vivo. Here we show lack efficacy against berghei mice resulted from a combination poor plasma exposure reduced potency DHODH. For compounds containing naphthyl (DSM1) or...
Deleterious mutations in RS1 encoding retinoschisin are associated with X-linked juvenile retinoschisis (RS), a common form of macular degeneration males. The disorder is characterized by negative electroretinogram pattern and splitting the inner retina. To gain further insight into function protein its role cellular pathology RS, we have generated knockout mice deficient Rs1h , murine ortholog human gene. We show that pathologic changes hemizygous −/Y male evenly distributed across retina,...
Malaria is one of the leading causes severe infectious disease worldwide; yet, our ability to maintain effective therapy combat illness continually challenged by emergence drug resistance. We previously reported identification a new class triazolopyrimidine-based Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors with antimalarial activity, discovery lead series and novel target for development. Active compounds from contained triazolopyrimidine ring attached an aromatic...
A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) NF54 (chloroquine-susceptible as well cytotoxicity. Synthesis structure–activity studies number promising with selective activity. One these frontrunner compounds, 15, was...
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel target for malaria, to enter clinical development. In an effort identify next generation of PI4K inhibitors, series optimized improve properties such as solubility and antiplasmodial potency across parasite life cycle, leading 2-aminopyrazine UCT943.
The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by novel chemical route and assessed in vitro activity against multidrug resistant strains of Plasmodium falciparum malaria infections mice. Here we describe the pathway to discovery potent class orally active 4(1H)-quinolone-3-diarylethers. initial prototype, ELQ-233, exhibited low nanomolar IC50 values all tested including clinical isolates harboring...
Abstract Background Modelling and simulation are being increasingly utilized to support the discovery development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance cytochrome P450 inhibition. This work was conducted generate an toolbox using standardized methods a set 45 drugs assess changes properties relation changing target product candidate profiles. Methods Ionization constants were...
The development of new antimalarial compounds remains a pivotal part the strategy for malaria elimination. Recent large-scale phenotypic screens have provided wealth potential starting points hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared real time, anyone was able to participate, patents not sought. chemical subseries found exhibit oral activity but contained labile ester that could be replaced...
Abstract The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5–8 million people in Latin America. disease characterised by an acute phase, which partially resolved immune system, but then develops as a chronic life-long infection. There consensus that front-line drugs benznidazole nifurtimox are more effective against stage both clinical experimental settings. However, confirmative studies have been restricted difficulties...
KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate H3K23 exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of to achieve therapeutic benefit has been a challenge. Here we describe identification highly potent, selective, orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from benzisoxazole series, which demonstrates anti-tumor...
A novel class of antimalarial pyrido[1,2-a]benzimidazoles were synthesized and evaluated for antiplasmodial activity cytotoxicity following hits identified from screening commercially available compound collections. The most active these, TDR86919 (4c), showed improved in vitro vs the drug-resistant K1 strain Plasmodium falciparum relative to chloroquine (IC(50) = 0.047 μM v 0.17 μM); potency was retained against a range drug-sensitive strains, with negligible mammalian (L-6) cell line...
An aminomethylthiazole pyrazole carboxamide lead 3 with good in vitro antiplasmodial activity [IC(50): 0.08 μM (K1, chloroquine and multidrug resistant strain) 0.07 (NF54, sensitive strain)] microsomal metabolic stability was identified from whole cell screening of a SoftFocus kinase library. Compound also exhibited vivo the P. berghei mouse model at 4 × 50 mg/kg administration via oral route, showing 99.5% 9 days survival showed low cytotoxicity. Pharmacokinetic studies rats revealed...
A new bispyrroloiminoquinone alkaloid, tsitsikammamine C (1), displayed potent in vitro antimalarial activity with IC50 values of 13 and 18 nM against chloroquine-sensitive (3D7) chloroquine-resistant (Dd2) Plasmodium falciparum, respectively. Tsitsikammamine (1) selectivity indices >200 HEK293 cells inhibited both ring trophozoite stages the malaria parasite life cycle. Previously reported compounds makaluvamines J (2), G (3), L (4), K (5) damirones (6) B (7) were also isolated from same...
The emergence of drug-resistant malaria parasites continues to hamper efforts control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment malaria, and selective inhibitor (DSM265) Plasmodium enzyme is currently in clinical development. With goal identifying backup compound DSM265, we explored replacement SF5-aniline moiety DSM265 with series CF3-pyridinyls while maintaining core triazolopyrimidine scaffold. This effort led...