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Small Molecule Degraders of Tryptophan 2,3-Dioxygenase Enzyme (TDO) as Novel Treatments for Neurodegenerative Disease

Award Number: F31AG084329
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Small Molecule Degraders of Tryptophan 2,3-Dioxygenase Enzyme (TDO) as Novel Treatments for Neurodegenerative Disease - Neurodegenerative disease is an emerging public health crisis with Alzheimer’s disease (AD) being the 6th leading cause of death that affects 6.7M patients in the US alone. To date, no curative agents have been identified, and commonly prescribed therapeutics (donepezil, memantine) remediate symptoms, but are wholly ineffective at treating the underlying condition. Contemporary literature suggests that the build-up of neurotoxic kynurenine pathway (KP) metabolites might promote AD pathogenesis. One such neurotoxic KP metabolite, quinolinic acid (QUIN), agonizes the N-methyl-D-aspartate (NMDA) receptor and exerts broad-spectrum neurotoxicity, particularly in the hippocampus and striatum. Notably, neurodegeneration of the hippocampus is a hallmark of AD dementia. As such, regulation of QUIN biosynthesis offers an attractive approach to the treatment of AD. In the proposed research, we aim to regulate QUIN biosynthesis within the CNS by targeting the tryptophan 2,3-dioxygenase enzyme (TDO). TDO is a tetrameric heme-dependent enzyme responsible for the rate-determining first step of the KP. Rather than target the heme-dependent TDO active site, we aim to target a non-catalytic binding site that plays a critical role in the stability of the active tetramer. The central hypothesis of the proposed research is that small molecule-mediated destabilization of this non-catalytic site constitutes a novel approach to the regulation of neurotoxic KP metabolites, and thus a novel approach to the treatment of AD. We will test this hypothesis through two complementary aims. Aim 1 will utilize computational modeling and chemical synthesis to deliver non-catalytic site-selective small molecule degraders of TDO. Aim 2 will assess the therapeutic viability of compounds generated in aim 1 through a series of biochemical assays. Specifically, the TDO degrading effects of each compound will be measured via an ELISA assay, quantitative KP metabolite profiling, and isothermal calorimetry. The pharmacokinetic profiles of select compounds will be assessed via MDCK and microsomal stability assays. Together, these aims will deliver CNS-penetrant TDO degraders and characterize their pharmacological effects on the propagation of neurotoxic KP metabolites. The ligands identified could serve as valuable tool compounds for follow-up studies in translational neuroscience to interrogate the role of KP metabolites in AD pathogenesis.


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: 2025 ( Subtotal = $49,338 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	000	2	12/27/2024	NON-COMPETING CONTINUATION	$47,694
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	001	2	6/23/2025	NON-COMPETING CONTINUATION	$1,644
														Subtotal = $49,338

Issue Date FY: 2023 ( Subtotal = $47,694 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	001	1	8/15/2023	NEW	$0
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Aging Research	000	1	8/15/2023	NEW	$47,694
														Subtotal = $47,694

Grand Total All Awards = $97,032

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Small Molecule Degraders of Tryptophan 2,3-Dioxygenase Enzyme (TDO) as Novel Treatments for Neurodegenerative Disease

Award Number: F31AG084329

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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