Dataset Information

BMS-708,163 targets presenilin and lacks notch-sparing activity.

ABSTRACT: The "Notch-sparing" ?-secretase inhibitor (GSI) BMS-708,163 (Avagacestat) is currently in phase II clinical trials for Alzheimer's disease. Unlike previously failed GSIs, BMS-708,163 is considered to be a promising drug candidate because of its reported Notch-sparing activity for the inhibition of A? production over Notch cleavage. We now report that BMS-708,163 binds directly to the presenilin-1 N-terminal fragment and that binding can be challenged by other pan-GSIs, but not by ?-secretase modulators. Furthermore, BMS-708,163 blocks the binding of four different active site-directed GSI photoaffinity probes. We therefore report that this compound acts as a nonselective ?-secretase inhibitor.

SUBMITTER: Crump CJ

PROVIDER: S-EPMC3470910 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

BMS-708,163 targets presenilin and lacks notch-sparing activity.

Crump Christina J CJ Castro Suita V SV Wang Feng F Pozdnyakov Nikolay N Ballard T Eric TE Sisodia Sangram S SS Bales Kelly R KR Johnson Douglas S DS Li Yue-Ming YM

Biochemistry 20120904 37

The "Notch-sparing" γ-secretase inhibitor (GSI) BMS-708,163 (Avagacestat) is currently in phase II clinical trials for Alzheimer's disease. Unlike previously failed GSIs, BMS-708,163 is considered to be a promising drug candidate because of its reported Notch-sparing activity for the inhibition of Aβ production over Notch cleavage. We now report that BMS-708,163 binds directly to the presenilin-1 N-terminal fragment and that binding can be challenged by other pan-GSIs, but not by γ-secretase mod ...[more]

PMID: 22931393

Similar Datasets

Project description:BackgroundAs meropenem is a restricted antimicrobial, lessons learned from its real-life usage will be applicable to antimicrobial stewardship (AMS) more generally.ObjectivesTo retrospectively evaluate meropenem usage at our institution to identify targets for AMS interventions.MethodsPatients receiving meropenem documented with an 'alert antimicrobial' form at two tertiary care UK hospitals were identified retrospectively. Clinical records and microbiology results were reviewed.ResultsA total of 107 adult inpatients receiving meropenem were identified. This was first-line in 47% and escalation therapy in 53%. Source control was required in 28% of cases after escalation, for predictable reasons. Those ultimately requiring source control had received more prior antimicrobial agents than those who did not (P = 0.03). Meropenem was rationalized in 24% of cases (after median 4 days). Positive microbiology enabled rationalization (OR 12.3, 95% CI 2.7-55.5, P = 0.001) but rates of appropriate sampling varied. In cases with positive microbiology where meropenem was not rationalized, continuation was retrospectively considered clinically and microbiologically necessary in 8/40 cases (0/17 empirical first-line usage). Rationalization was more likely when meropenem susceptibility was not released on the microbiology report (OR 5.2, 95% CI 1.3-20.2, P = 0.02). Input from an infection specialist was associated with a reduced duration of meropenem therapy (P < 0.0001). Early review by an infection specialist has the potential to further facilitate rationalization.ConclusionsIn real-life clinical practice, core aspects of infection management remain tractable targets for AMS interventions: microbiological sampling, source control and infection specialist input. Further targets include supporting rationalization to less familiar carbapenem-sparing antimicrobials, restricting first-line meropenem usage and selectively reporting meropenem susceptibility.

Dataset Information

BMS-708,163 targets presenilin and lacks notch-sparing activity.

Publications

BMS-708,163 targets presenilin and lacks notch-sparing activity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets