Tuesday, June 24, 2025 6/24/2025

Diversity Supplement for Imani McDonald - Developing Autophagy-Targeting Chimeras and Optimizing Cell Penetration of Large-Molecule Therapeutics

Award Number: R35GM148407
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Diversity Supplement for Imani McDonald - Developing Autophagy-Targeting Chimeras and Optimizing Cell Penetration of Large-Molecule Therapeutics - The Kritzer lab focuses on inhibiting protein-protein interactions involved in autophagy. Autophagy is a protein degradation pathway that is active in all human cells, and inhibiting autophagy shows promise as a therapy for late-stage cancers especially in combination with DNA-damaging chemotherapies. Autophagy research and drug development currently rely on compounds that inhibit autophagy indirectly. Better, more specific inhibitors of autophagy would be broadly adopted. A large amount of genetics and cell biology work supports that inhibiting the LC3/GABARAP family of proteins can block autophagy selectively. In one series of projects, we will develop novel stapled peptide and small molecule inhibitors of LC3/GABARAP and evaluate them in models of late-stage cancers and other diseases. Because of our expertise in compounds that bind LC3/GABARAP proteins, we also propose to evaluate related compounds as autophagy-targeting chimeras (AUTACs). These compounds could be used to selectively degrade any proteins in the cell, similar to proteolysis-targeting chimeras (PROTACs) but potentially more versatile and easier to develop. Based on strong preliminary data that validate the AUTAC concept, we will develop novel AUTACs and demonstrate their ability to degrade endogenous proteins, unlocking a broad new area for drug development in targeted protein degradation. Over the course of developing stapled peptides as autophagy modulators, the Kritzer lab encountered a common problem in the field: how to measure the amount that actually reaches the cytosol. In an independent series of projects, the Kritzer lab has developed novel assays that quantitate the cytosolic penetration of large-molecule therapeutics. In this proposal, we describe new opportunities to address challenging problems in drug development for large-molecule therapeutics. We describe new methods to measure penetration to different cellular compartments in any cell type, including primary cells. We also describe a molecular evolution approach to develop a new “turn-on” assay that measures the real-time kinetics of cytosolic penetration. We describe pooled CRISPR screens to reveal the cellular components that mediate endosomal escape. Finally, we describe a novel screening platform that will allow us to screen thousands to millions of molecules at a time for those that are most cell-penetrant; the new screen will be incorporated into a design-test-learn cycle to produce data-driven design algorithms for cytosol-penetrant molecules. All together, these data will represent a huge leap in our understanding of structure-penetration relationships for several classes of large-molecule therapeutics.


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 = $0 )
2025	2024	TRUSTEES OF TUFTS COLLEGE	80 GEORGE ST	MEDFORD	MA	02155	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	6/3/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	11/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $832,770 )
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Biomedical Research and Research Training	003	2	7/29/2024	NON-COMPETING CONTINUATION	$63,312
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	2/16/2024	NON-COMPETING CONTINUATION	$569,812
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	4/22/2024	SUPPLEMENT FOR EXPANSION	$70,196
2024	2024	TRUSTEES OF TUFTS COLLEGE	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Biomedical Research and Research Training	002	2	5/1/2024	SUPPLEMENT FOR EXPANSION	$129,450
														Subtotal = $832,770

Issue Date FY: 2023 ( Subtotal = $579,024 )
2023	2023	TRUSTEES OF TUFTS COLLEGE INC	169 HOLLAND ST	SOMERVILLE	MA	02144	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	2/10/2023	NEW	$579,024
														Subtotal = $579,024

Grand Total All Awards = $1,411,794

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Diversity Supplement for Imani McDonald - Developing Autophagy-Targeting Chimeras and Optimizing Cell Penetration of Large-Molecule Therapeutics

Award Number: R35GM148407

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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