Publications by authors named "I T Collie"
The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.
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- While treatments for human African trypanosomiasis (HAT) have advanced, new drugs are still needed as eradication becomes feasible.
- Researchers developed 2,4-diaminothiazoles that show strong effectiveness against the parasite causing HAT, using phenotypic screening to enhance their drug-like properties.
- Despite promising initial results, the compounds failed to effectively treat the severe stage of the disease due to a shift from a destructive to a static action mechanism, highlighting a need for drugs that actively kill the parasite.
Article Synopsis
- - MAT2a is an enzyme that produces adenosylmethionine (SAM) from methionine and ATP, and is a potential target for treating cancers with co-deletion of the p16 and MTAP genes.
- - Researchers developed MAT2a inhibitors through fragment-based lead generation and structural design, creating a new series of arylquinazolinone compounds.
- - One of these inhibitors effectively reduced SAM-related methylation and slowed the growth of MTAP-null cancer cells, also showing promise in inducing antitumor responses in animal models.
Background: While the ability to measure time correctly is crucial for adaptation to the external physical and social environment, to date, research on timing ability and its development in individuals with intellectual disability (ID) is unfortunately remarkably scarce.
Aims: In the present study, we investigated the ability of individuals with mild ID to estimate durations and the development of this ability from 11 to 19 years, in comparison to typically developing (TD) individuals.
Methods And Procedures: Participants with mild ID and TD participants matched on chronological age completed two temporal tasks: (1) a temporal bisection of auditory stimuli, in which they had to decide whether arbitrary stimulus duration was more similar to the short (200 ms) or the long (800 ms) standard previously learned, and (2) a temporal categorization of familiar actions, in which short, medium or long target durations had to be paired with one of three comparison action durations.
The TRAF2 and NCK interacting kinase (TNIK) has been proposed to play a role in cytoskeletal organization and synaptic plasticity and has been linked, among others, to neurological disorders. However, target validation efforts for TNIK have been hampered by the limited kinase selectivity of small molecule probes and possible functional compensation in mouse models. Both issues are at least in part due to its close homology to the kinases MINK1 (or MAP4K6) and MAP4K4 (or HGK).
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