Fragment-based discovery of step modulators in alzheimer's disease

Active Project Grant Awarded Last action

Award ID
RF1AG087011
Recipient
Awarding agency
Obligated
$5,782,740

Award facts

Assistance listing
93.866 Aging Research
Completion date 84% complete
Place of performance
La Jolla, CA 92037, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific protein tyrosine phosphatase (PTP) and a novel therapeutic target for alzheimer's disease (ad), a debilitating neurodegenerative disorder for which no cure currently exists. Multiple studies indicate that levels of STEP are elevated in ad and other neurodegenerative and neuropsychiatric disorders, including parkinson's disease, schizophrenia, and fragile X syndrome. The data suggest that increased STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits in these devastating diseases. Crossing STEP KO mice with mouse models of ad, schizophrenia, or fragile X syndrome completely reversed the cognitive and behavioral deficits, generating progeny with lower STEP levels indistinguishable from WT mice. Similar effects were observed when STEP was pharmacologically inhibited by our tool compound TC-2153. These studies validate STEP as a novel drug target for the treatment of ad and other neurodegenerative and neuropsychiatric disorders. TC-2153 is the only reported STEP inhibitor with cellular and in vivo activity. However, TC-2153 and similar compounds are known to react with cellular thiols and modify DNA, precluding this inhibitor from further preclinical studies. Other reported STEP inhibitors suffer from poor selectivity for STEP and lack of efficacy under physiological conditions. To overcome these typical challenges for inhibitors targeting ptps - enzymes that have a highly conserved and highly charged active site - we set out to discover small molecules that bind to less conserved, allosteric sites in STEP. Using innovative fragment-based screening technologies, we identified 19 fragments, low molecular weight compounds adhering to the "rule of 3", that selectively bind to novel, less conserved sites in STEP with up to single digit micromolar affinity. These fragments are ideal starting points for generating STEP-targeted degraders such as proteolysis targeting chimeras (PROTACS) with physicochemical properties suitable for crossing the blood-brain barrier (BBB). In fact, in preliminary experiments we have demonstrated that a protac based on our best fragment can effectively reduce STEP levels in vivo. Based on these exciting results, we propose a STEP-targeted protein degradation approach as a therapeutic strategy in ad. In aim 1, we will optimize our fragment binders for ligand efficiency and STEP selectivity. In aim 2, we will generate STEP PROTACS from the most promising binders, assess them in our established testing funnel, and optimize them for drug metabolism and pharmacokinetics (DMPK), pharmacodynamics (PD), and toxicity (TOX) properties. The goal is to generate non-toxic STEP degraders with exposure and efficacy in the brain. In aim 3, we will test whether candidate PROTACS are able to improve cognition in mouse ad models. Our studies are designed to provide proof-of-concept (POC) for STEP degraders as novel therapeutics in ad. We expect to develop at least one lead series and one backup series of effective PROTACS that are ready for preclinical development towards a first-in-class early treatment option for ad.

Transactions

Action Obligated Date
Amendment Fragment-based discovery of step modulators in alzheimer's disease administrative supplement $111,976
Amendment $2,835,382
Original award Fragment-based discovery of step modulators in alzheimer's disease administrative supplement $2,835,382

Subawards

Subrecipient Amount Awarded
Research Foundation Of The City University Of New York Dr. Keedy will direct X-ray crystallography and HDX-MS experiments at the ASRC to help characterize the binding of new allosteric ligands to STEP. $78,153
University Of California, San Diego Part 1: Test cell lines expressing STEP for signaling activity and compound-related modulation. 1.Analyze functional endpoints 2.Quantitate products by… $15,092
Research Foundation Of The City University Of New York Dr. Keedy will direct X-ray crystallography and HDX-MS experiments at the ASRC to help characterize the binding of new allosteric ligands to STEP. $78,153
University Of California, San Diego Part 1: Test cell lines expressing STEP for signaling activity and compound-related modulation. 1.Analyze functional endpoints 2.Quantitate products by… $46,892
Research Foundation Of The City University Of New York Dr. Keedy will direct X-ray crystallography and HDX-MS experiments at the ASRC to help characterize the binding of new allosteric ligands to STEP. $78,153

Quick answers

Who received award RF1AG087011?

RF1AG087011 was awarded to Sanford Burnham Prebys Medical Discovery Institute by National Institute on Aging (National Institutes of Health) on May 15, 2024.

How much is award RF1AG087011 worth?

$5,782,740 has been obligated on RF1AG087011.

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