Monday, June 30, 2025 6/30/2025

Therapeutic Targeting Mitochondrial C1 Metabolism

Award Number: R01CA250469
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Therapeutic Targeting Mitochondrial C1 Metabolism - ABSTRACT Metabolic reprogramming is an important hallmark of cancer. Of the altered metabolic pathways associated with malignancy, one-carbon (C1) metabolism is particularly notable. The 3-carbon of serine is the major C1 donor for de novo synthesis of purines and thymidylate in the cytosol, and the primary catabolic pathway for serine and synthesis of glycine occurs in the mitochondria. The mitochondrial C1 pathway also generates reducing equivalents and is an important source of ATP. The first enzyme of the mitochondrial C1 pathway, serine hydroxymethyltransferase (SHMT) 2, is an oncodriver which is upregulated in a substantial number of cancers. Growing evidence suggests that SHMT2 could be an independent prognostic factor and an important therapeutic target for cancer. We discovered novel 5-substituted pyrrolo[3,2-d]pyrimidine compounds AGF291, AGF347, and AGF359. Following their internalization by the proton-coupled folate transporter (PCFT), these compounds inhibit mitochondrial C1 metabolism at SHMT2, with direct secondary inhibitions of cytosolic targets in de novo purine (DNP) biosynthesis (at 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase) and SHMT1. Our compounds inhibit proliferation of epithelial ovarian cancer, non-small cell lung cancer, colorectal cancer, and pancreatic cancer (PaC) cells, suggesting their potential as broad-spectrum anti-tumor agents. AGF347 exhibited significant in vivo antitumor efficacy with potential for complete responses against both early and upstage PaC xenograft models. We posit that our novel compounds offer an entirely new approach for treating cancer. Our objective is to optimize our lead structures for tumor targeting via PCFT and inhibition of mitochondrial and cytosolic C1 metabolism at modest doses with minimal toxicity. We will use PaC as a disease prototype for further development of our novel multi-targeted inhibitors. In Aim 1, we will synthesize up to 100 compounds based on lead compounds to optimize uptake by tumors, and inhibition of SHMT2 and cytosolic pathways including DNP biosynthesis. In Aim 2, we will test analogs from Aim 1 for antitumor potencies toward clinically relevant PaC cell lines, tumor selectivity and plasma membrane and mitochondrial drug transport, drug metabolism, and inhibition of SHMT2 and cytosolic pathways including DNP biosynthesis. We will measure downstream impacts on mTOR signaling, mitochondrial respiration, glutathione pools, and reactive oxygen species. In Aim 3, we will evaluate pharmacokinetics, tolerability, and in vivo antitumor activities of compounds from Aims 1 and 2 by toxicity/efficacy trials with human PaC cell line xenograft and PDX models, and with the KPC mouse PaC model. Our lead analogs are “first-in-class” and our proposed studies will afford optimized compounds with the best balance of selective tumor targeting and anti-tumor efficacy, resulting from inhibition of SHMT2 and downstream anabolic pathways. We anticipate developing SHMT2/DNP-targeted compounds for IND submission and clinical trials based on our studies.


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 = $614,438 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	001	5	6/12/2025	NON-COMPETING CONTINUATION	$61,444
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	5	12/13/2024	NON-COMPETING CONTINUATION	$552,994
														Subtotal = $614,438

Issue Date FY: 2024 ( Subtotal = $583,716 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$30,722
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	4	12/22/2023	NON-COMPETING CONTINUATION	$552,994
														Subtotal = $583,716

Issue Date FY: 2023 ( Subtotal = $602,150 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	3	12/12/2022	NON-COMPETING CONTINUATION	$552,994
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	001	3	3/17/2023	NON-COMPETING CONTINUATION	$49,156
														Subtotal = $602,150

Issue Date FY: 2022 ( Subtotal = $602,150 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	001	2	6/7/2022	NON-COMPETING CONTINUATION	$49,157
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	2	12/16/2021	NON-COMPETING CONTINUATION	$552,993
														Subtotal = $602,150

Issue Date FY: 2021 ( Subtotal = $641,436 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Cancer Treatment Research	000	1	1/1/2021	NEW	$641,436
														Subtotal = $641,436

Grand Total All Awards = $3,043,890

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Therapeutic Targeting Mitochondrial C1 Metabolism

Award Number: R01CA250469

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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