Development of a MT-stabilizing agent for the treatment of tauopathies

Active Cooperative Agreement Awarded Last action

Award ID
U01AG088051
Recipient
Awarding agency
Obligated
$11,441,923

Award facts

Assistance listing
93.866 Aging Research
Completion date 72% complete
Place of performance
La Jolla, CA 92093, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
A group of neurodegenerative diseases referred to as tauopathies, which includes alzheimer's disease (ad), are characterized by the presence within brain neurons of inclusions comprised of hyperphosphorylated forms of TAU protein. TAU is normally a microtubule (MT)-associated protein that appears to provide stability to MTS in axons, and excessive phosphorylation of TAU in tauopathies promotes its disengagement from MTS and misfolding into oligomeric and fibrillar structures. This results in increased MT dynamicity, reduced MT density and altered axonal transport in transgenic (TG) mouse tauopathy models, with evidence of similar MT deficits in ad brain that likely contribute to neurodegeneration. We previously demonstrated that administration of the brain-penetrant MT- stabilizing natural product, epothilone d (epod), to TG tauopathy mice resulted in dramatic improvements in several key endpoints, including increased MT density, reduced axonal dystrophy, diminished TAU pathology and a lowering of neuron loss with improved cognitive performance. Although epod progressed to a small phase 1B clinical trial in ad patients, its future clinical advancement is uncertain. Thus, there would be considerable value in identifying alternative MT- stabilizing agents that could undergo more thorough testing in ad and tauopathy patients. Towards this end, we evaluated additional MT-stabilizing compounds from different classes, with the goal of identifying alternative and potentially improved candidates for development as disease-modifying drugs for ad and other tauopathies. This effort led to the identification of a preferred subset of brain- penetrant MT-stabilizing triazolopyrimidines (tpds) that compared to epod and other MT-stabilizing natural products, offer notable advantages, including oral bioavailability and easier synthesis. With NIH/NIA support (U01/AG061173), a systematic exploration of the structure-activity relationships of tpds ultimately led to the identification of a structurally novel compound (cndr-51997) that exhibits improved MT-stabilizing activity and pharmacokinetic profile. Based on extensive characterization of this compound, including efficacy testing in two different ad mouse models, we believe that cndr- 51997 qualifies as a candidate compound for further development. Accordingly, the primary objectives of this three-year, late-stage U01 proposal are to develop cndr-51997 through IND-enabling studies and submit an IND application.

Transactions

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Subawards

Subrecipient Amount Awarded
The Trustees Of The University Of Pennsylvania Mod: 150,585 Sub: 153,049.00 Scope of Work Dr. Kurt Brunden, Research Professor at the University of Pennsylvania, is a Co-PI on this late-stage U01 grant… $303,634

Quick answers

Who received award U01AG088051?

U01AG088051 was awarded to University Of California, San Diego by National Institute on Aging (National Institutes of Health) on September 1, 2024.

How much is award U01AG088051 worth?

$11,441,923 has been obligated on U01AG088051.

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