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Discovery of small molecule activators of the Slack potassium channel for use as cell-based probes for the study of fragile X syndrome

Award Number: R21MH125257
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2020
PERIOD OF PERFORMANCE END DATE: 10/31/2023

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Discovery of small molecule activators of the Slack potassium channel for use as cell-based probes for the study of fragile X syndrome - ABSTRACT Ion channels are water-filled pores that mediate the passage of ions across cell membranes, thereby contributing to a multitude of essential cellular functions. Though many currently available drugs work via interaction with ion channels, the vast majority of ion channels lack the potent and selective small molecule tool compounds necessary to properly study their therapeutic potential. The Slack channel, encoded by KCNT1, is a member of the Slo family of potassium channels; this family of channels has a diversity of roles throughout the body, notably including the regulation of neuronal activity. Recently, it was discovered that an RNA-binding protein known as Fragile X mental retardation protein (FMRP) binds to and activates Slack channels. Gene silencing of fragile X mental retardation type 1 (FMR1) leads to an absence of FMRP and causes fragile X syndrome (FXS), an X- linked disorder that is the most common known cause of inherited intellectual disability (ID) and monogenic autism spectrum disorder (ASD). Studies in animals have shown that Slack activity is critical for certain types of higher cognitive function. Thus, we hypothesize that diminished Slack activity in FXS patients due to the absence of FMRP contributes to the ID associated with the disease, and normalization of Slack activity via pharmacotherapy represents a potential treatment approach. Unfortunately, there are presently no known potent and selective small molecule Slack activator probes available to investigate this hypothesis. Studies with such probes represent an essential, early step in helping to validate this novel approach to FXS therapy. The proposed research will employ a medicinal chemistry hit optimization approach to develop structure activity relationships (SAR) in two distinct chemical scaffolds that we discovered through a high-throughput screening (HTS) approach. We will assess the Slack activator potency and efficacy of our newly synthesized compounds using an HTS-compatible Tl+ flux assay and the “gold standard” method for measuring ion channel activity, voltage- clamp electrophysiology. We will test the capacity of our compounds to increase the activity of Slack channels in Slack-expressing HEK-293 cells where FMRP expression has been knocked out as well as in neurons isolated from Fmr1-/y mice. We will evaluate the selectivity of compounds versus Slo family members, other ion channels, and ultimately a broad panel of molecular targets. We will also monitor our compounds with regard to solubility, membrane permeability, and potential for cellular efflux to ensure that our probes will not be limited by poor attributes in these areas. To reach our goal efficiently, we have designed a thoughtful critical path that can serve us with compound progression decisions and ensure a holistic evaluation of compounds. Completion of our aims will enable us to reach our end goal of developing high quality Slack activator cell-based probes that may be used by the community to study activation of this target as a novel treatment for FXS.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$18,983 )
2024	2022	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Mental Health Research Grants	000	2	4/5/2024	NON-COMPETING CONTINUATION	-$18,983
														Subtotal = -$18,983

Issue Date FY: 2022 ( Subtotal = $189,824 )
2022	2022	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Mental Health Research Grants	001	2	6/21/2022	NON-COMPETING CONTINUATION	$18,983
2022	2022	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Mental Health Research Grants	000	2	10/28/2021	NON-COMPETING CONTINUATION	$170,841
														Subtotal = $189,824

Issue Date FY: 2021 ( Subtotal = $238,524 )
2021	2021	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Mental Health Research Grants	000	1	11/27/2020	NEW	$238,524
														Subtotal = $238,524

Grand Total All Awards = $409,365

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Discovery of small molecule activators of the Slack potassium channel for use as cell-based probes for the study of fragile X syndrome

Award Number: R21MH125257

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2020

PERIOD OF PERFORMANCE END DATE: 10/31/2023

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