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Chemical and Structural Approaches to Study Energy Homeostasis Pathways in Cancer and Metabolic disorders

Award Number: R35GM124838
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The overall research in the Lazarus Lab revolves around studying energy and protein homeostasis as it relates to human disease using chemical biology and structural biology. We have several multidisciplinary projects around this topic, including studying the ULK family of autophagy kinases and pseudokinases, lysine metabolism disorders, and other kinases related to diabetes and cancer. Over the last 4 years, we have used crystallography and chemical biology to help develop highly potent inhibitors of the metabolic sensor O-GlcNAc transferase, solved the first structures and identify the first chemical probes of the ULK pseudokinase linked to schizophrenia ULK4, and helped elucidate the first structure of an enzyme in the lysine metabolic pathway DHTKD1. Our goals over the next five-year period include further understanding of the ULK family of kinases. ULK1 and ULK2 are the main initiating enzymes for the autophagy pathway, a conserved metabolic pathway whereby cellular components get degraded for quality control and energy generation during starvation. The pathway is thought to be critical in diseases ranging from cancer to Alzheimer’s disease, yet there are still major gaps in our understanding of the pathway. What happens to cells when you inhibit autophagy at different stages of the pathway in different disease models using selective probes? What is the role of the mysterious family member ULK4, which has no catalytic activity but binds ATP with nanomolar potency and likely has a function for the ATP binding. Another major goal involves the lysine metabolic pathway, in which several inborn errors of metabolism are found. How do the enzymes in this pathway function, and can inhibiting other enzymes in this pathway block the toxic buildup of intermediates that arise in glutaric aciduria patients? The overall vision of the research program is to develop chemical probes and obtain high-resolution crystal structures to better understand key enzymes in these metabolic pathways and determine if they are therapeutic targets for human diseases. Within the context of the Mount Sinai research community, we are well-positioned to collaborate with our colleagues to leverage our strength in chemical and structural biology to provide molecular understanding that synergizes with our colleagues’ expertise in human biology or medicinal chemistry, like our overarching collaboration with the Drug Discovery Institute here and our collaborations that involve cancer, genetic diseases, diabetes, and neurodegeneration. As new opportunities arise, we can provide our expertise in the molecular underpinnings of glycosyltransferases, kinases and pseudokinases, and protein degradation pathways to develop new projects supported by the MIRA funding, while still focusing on the core projects described above.


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	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	8	11/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $464,453 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	8	7/26/2024	NON-COMPETING CONTINUATION	$464,453
														Subtotal = $464,453

Issue Date FY: 2023 ( Subtotal = $638,797 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	004	7	7/31/2023	SUPPLEMENT FOR EXPANSION	$122,532
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	6	6/19/2023	SUPPLEMENT FOR EXPANSION	-$24,415
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	6	2/20/2023	SUPPLEMENT FOR EXPANSION	$76,227
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	003	7	7/24/2023	NON-COMPETING CONTINUATION	$464,453
2023	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	002	5	6/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $638,797

Issue Date FY: 2022 ( Subtotal = $464,453 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	6	7/8/2022	COMPETING CONTINUATION	$464,453
														Subtotal = $464,453

Issue Date FY: 2021 ( Subtotal = $423,479 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	5	7/21/2021	NON-COMPETING CONTINUATION	$423,479
														Subtotal = $423,479

Issue Date FY: 2020 ( Subtotal = $423,479 )
2020	2020	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	4	7/30/2020	NON-COMPETING CONTINUATION	$423,479
														Subtotal = $423,479

Issue Date FY: 2019 ( Subtotal = $804,854 )
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	001	3	9/9/2019	SUPPLEMENT FOR EXPANSION	$381,375
2019	2019	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	3	7/26/2019	NON-COMPETING CONTINUATION	$423,479
														Subtotal = $804,854

Issue Date FY: 2018 ( Subtotal = $423,479 )
2018	2018	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	2	7/30/2018	NON-COMPETING CONTINUATION	$423,479
														Subtotal = $423,479

Issue Date FY: 2017 ( Subtotal = $402,629 )
2017	2017	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Biomedical Research and Research Training	000	1	9/18/2017	NEW	$402,629
														Subtotal = $402,629

Grand Total All Awards = $4,045,623

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Chemical and Structural Approaches to Study Energy Homeostasis Pathways in Cancer and Metabolic disorders

Award Number: R35GM124838

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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