A5059880322- Parasitic Diseases Research and Treatment
- Heat shock proteins research
- Parasite Biology and Host Interactions
- Parasites and Host Interactions
- Insects and Parasite Interactions
- Mosquito-borne diseases and control
- Carbohydrate Chemistry and Synthesis
- Toxin Mechanisms and Immunotoxins
- Endoplasmic Reticulum Stress and Disease
- Malaria Research and Control
- Quinazolinone synthesis and applications
- Asymmetric Synthesis and Catalysis
- Microbial infections and disease research
- Infectious Diseases and Mycology
- Synthetic Organic Chemistry Methods
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Herpesvirus Infections and Treatments
- Mycobacterium research and diagnosis
- Fluorine in Organic Chemistry
- Synthesis and Biological Evaluation
- thermodynamics and calorimetric analyses
- ATP Synthase and ATPases Research
- Bacteriophages and microbial interactions
- Endometriosis Research and Treatment
Drugs & Diagnostics for Tropical Diseases
2013-2025
Biogen (United States)
2007-2012
Medicina
2010
Forma Therapeutics (United States)
2004-2006
Ono Pharmaceutical (United States)
2004
Magna Graecia University
2001
ETH Zurich
1998
ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTADDITION / CORRECTIONThis article has been corrected. View the notice.Heat Shock Protein 90: Inhibitors in Clinical TrialsMarco A. Biamonte*†, Ryan Van de Water†, Joseph W. Arndt‡, Robert H. Scannevin‡, Daniel Perret†, and Wen-Cherng Lee‡View Author Information† Biogen Idec, 5200 Research Place, San Diego, California 92122‡ Cambridge, Massachusetts 02142*To whom correspondence should be addressed. Phone: (858) 401-5082. Fax: 795-9642. E-mail:...
Heat shock protein 90 (Hsp90) is a molecular chaperone implicated in stabilizing the conformation and maintaining function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 their conformation, stability, maturation than normal counterparts. Furthermore, recent data show that exists an activated form malignant cells but latent inactive tissues, suggesting inhibitors selective for could provide high therapeutic index. Hence, emerging as exciting new target...
We report on the discovery of benzo- and pyridino- thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions aromatic ring with a 7'-substituent essential for activity. Some these compounds exhibit low nanomolar inhibition activity in Her-2 degradation assay (28-150 nM), good aqueous solubility, oral bioavailability profiles mice. In vivo efficacy experiments demonstrate that this class inhibit tumor growth an N87...
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding and stabilizing multiple intracellular proteins that have roles cell activation proliferation. Many Hsp90 client tumor cells are mutated or overexpressed oncogenic driving cancer growth, leading to the acceptance of as potential therapeutic target for cancer. Because several signal transduction molecules dependent on function also innate adaptive immune system, we investigated mechanism by which inhibiting leads...
Abstract Accurate and reliable diagnostic tools are an essential requirement for neglected tropical diseases (NTDs) programmes. However, the NTD community has historically underinvested in development improvement of tools, potentially undermining successes achieved over last 2 decades. Recognizing this, WHO, its newly released draft roadmap 2021–2030, identified diagnostics as one four priority areas requiring concerted action to reach 2030 targets. As a result, WHO established Diagnostics...
Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and substantially more potent in vitro vivo than the first 14 (BIIB021) that completed phase II clinical trials. 40 an Hsp90α binding assay (IC50 = 1.1 vs 5.1 nM) as well its ability to degrade Her-2 MCF-7 cells (EC50 38 nM). In mouse model gastric tumors (N87), stops tumor growth at 5...
The DDTD biplex A RDT prototype was easy to use in the field but evaluation of its performance relative commercially available Ov16 SD Bioline will require additional research. high seroprevalence suggests ongoing O. volvulus transmission around Maridi Dam. Therefore, strengthening onchocerciasis elimination program should be a public health priority.
Background: Point-of-care diagnostic tests are essential for confirming Onchocerca volvulus transmission in remote, resource-limited, onchocerciasis-endemic communities. In Maridi, South Sudan, we field-tested a novel "biplex A" rapid test (RDT) developed by Drugs & Diagnostics Tropical Diseases (DDTD), San Diego, California. Methods: February 2023, children aged 3-9 years were recruited from study sites at different distances the Maridi Dam, known blackfly breeding site. O. antibodies...
Orally active Hsp90 inhibitors are of interest as potential chemotherapeutic agents. Recently, fully synthetic 8-benzyladenines and 8-sulfanyladenines such 4 were disclosed inhibitors, but these compounds not water soluble consequently have unacceptably low oral bioavailabilities. We now report that water-solubility can be achieved by inserting an amino functionality in the N(9) side chain. This results potent, aqueous media, orally bioavailable. In HER-2 degradation assay, highest potency...
The selective heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) is currently in phase I/II clinical studies at numerous institutions. Heretofore, the biomarkers to detect 17-AAG bioactivity (Hsp70, Raf-1, and cyclin-dependent kinase 4) had be analyzed by Western blot of cellular samples, either from tumor biopsies or peripheral blood leukocytes, a method that both laborious invasive. We have identified two new [insulin-like growth factor binding protein-2...
Ivermectin-based mass drug administration (MDA) programs have achieved remarkable success towards the elimination of onchocerciasis and lymphatic filariasis. However, their full implementation has been hindered in Central Africa by occurrence ivermectin-related severe adverse events (SAEs) a subset individuals with high circulating levels Loa loa microfilariae. Extending MDA to areas coincident L. infection is problematic, inexpensive point-of-care tests for are acutely needed. Herein, we...
Several lines of evidence support the hypothesis that c-Jun N-terminal kinases (JNKs) play a critical role in wide range disease states including cell death (apoptosis)-related and inflammatory disorders (epilepsy, brain, heart renal ischemia, neurodegenerative diseases, multiple sclerosis, rheumatoid arthritis, bowel syndrome). The screening compound collection led to identification 2-(benzoylaminomethyl)thiophene sulfonamide (AS004509, I) as potent selective JNK inhibitor. Chemistry...
Loiasis, caused by the filarial nematode Loa loa, is endemic in Central and West Africa where about 10 million people are infected. There a scarcity of convenient, commercial diagnostics for L. loa. Microscopy requires trained personnel has low sensitivity, while serodiagnosis currently not standardized. Individual case management also important non-endemic countries to treat migrants, expatriates tourists. We retrospectively compared performance Antibody Rapid Test (RDT) ELISA pan-filarial...
As lymphatic filariasis (LF) programs move closer to established targets for validation elimination of LF as a public health problem, diagnostic tools capable supporting the needs are critical success. Known limitations existing make it challenging have confidence that program endpoints been achieved. In 2019, World Health Organization (WHO) Diagnostic Technical Advisory Group (DTAG) Neglected Tropical Diseases tasked with prioritizing including defining use-cases and target product profiles...
Buruli ulcer, caused by
In June 2021, the World Health Organization (WHO), recognizing need for new diagnostics to support control and elimination of onchocerciasis, published target product profiles (TPPs) tests that would two most immediate needs: (a) mapping onchocerciasis in areas low prevalence (b) deciding when stop mass drug administration programs. both instances, test should ideally detect an antigen specific live, adult O. volvulus female worms. The preferred format is a field-deployable rapid test. For...
Abstract According to ab‐initio calculations, the CF…︁HO H‐bond in 1,3‐diaxial 3‐fluorocyclohexanol is characterized by d (F…︁H) = 2.08 Å, and ∠ (F…︁HO) 138°, Δ E between 1.2 4.1 kcal/mol, depending upon reference system. Relative OH stretching frequency of axial cyclohexanol, shifted Δω 7 cm −1 . The rigid fluoro diols D‐ 4 L‐ were prepared from tetrahydroxy‐ p ‐benzoquinone 11 steps 1% overall yield. IR spectrum CCl soln. Δν for 44 equatorial group. A relatively strong intramolecular bond...
Abstract We report the development of a prototype rapid diagnostic test for Buruli ulcer, an ulcerative necrotizing skin disease caused by M. ulcerans . The was designed to detect mycolactone, metabolite unique chief technical challenge develop simple workflow extract trace amounts mycolactone from wound exudates collected with swab and, after concentration step, visualize means lateral flow assay. This achieved utilizing mouse monoclonal antibody specific and magnetic gold nanoshells....
Background Endemic to Central Africa, loiasis, caused by the vector-borne worm Loa loa , affects approximately 10 million individuals. Clinical manifestations include transient angioedema (Calabar swellings), migration of adult under eye conjunctiva (eye worm) and less specific general symptoms. Loiasis presents a significant public health challenge because L . -infected individuals can develop serious adverse events after taking ivermectin, drug used combat onchocerciasis. In this context,...
Three O. volvulus immunogenic peptide sequences recently discovered by microarray were adapted to a lateral flow assay (LFA). The LFA employs gold nanoshells as novel high-contrast reporter nanoparticles and detects serological response against the 3 peptides, found in OvOC9384, OvOC198, OvOC5528, respectively. When tested on 118 sera from infected patients 208 control sera, was 90%, 63%, 98% sensitive for each peptide, respectively, 99–100% specific vs samples healthy volunteers. Samples of...
The lack of a WHO-recommended strategy for onchocerciasis treatment with ivermectin in hypo-endemic areas co-endemic loiasis is an impediment to global elimination. New diagnostics (LoaScope; Loa antibody rapid test) and risk prediction tools may enable safe mass decisions areas. In 2017-2018, integrated mapping onchocerciasis, lymphatic filariasis (LF), loiasis, aimed at enabling decisions, was piloted Gabon. Three ivermectin-naïve departments suspected be were selected up 100 adults per...
The elimination of onchocerciasis through community-based Mass Drug Administration (MDA) ivermectin (Mectizan) is hampered by co-endemicity Loa loa, as individuals who are highly co-infected with loa parasites can suffer serious and occasionally fatal neurological reactions from the drug. test-and-not-treat strategy testing all participating in MDA has some operational constraints including cost limited availability LoaScope diagnostic tools. As a result, Antibody (Ab) Rapid Test was...
Abstract The title compounds D‐ 10 and L‐ were prepared from 1 in eight steps a combined overall yield of 41–49%.