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First in Class Small molecules to simultaneously inhibit protein translation and an immune checkpoint in cancers

Award Number: R01CA285468
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/11/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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First in Class Small molecules to simultaneously inhibit protein translation and an immune checkpoint in cancers - PROJECT SUMMARY Therapeutic approaches in cancer therapies have evolved from the use of highly toxic chemotherapy agents to precision medicine with well-defined targets and minimal toxicities. While precision medicine is highly desirable, its effectiveness depends on the presence of the activating agents and typically target a single pathway which is conducive to the development of drug resistance when alternative pathways and or feedback mechanisms are used. These limitations are best exemplified by anti-cancer therapies targeting the protein translation regulator mammalian Target Of Rapamycin (mTOR). Although these inhibitors show clear benefit in some cancers such as mantle cell lymphomas, Renal Cell Carcinoma and Tuberous Sclerosis Complex-related tumors they have limited efficacy as single agents in most other cancers due to compensatory feedback mechanisms. In addition, targeting components of the general protein translational machinery that are also essential for normal cell functions would likely contribute to normal tissue toxicity. Agents that could target simultaneously a number of limited key pathways essential for cancer cells progression and survival would thus be expected to decrease toxicity and resistance. To this Aim we have identified first in class small molecule inhibitors of hnRNP A18, a regulator of protein translation in cancer cells. hnRNP A18 targets transcripts that are involved in cancer progression, metastasis, angiogenesis, anti-apoptosis and tumor immune checkpoint. Our working hypothesis is that small molecule inhibitors of hnRNP A18 will inhibit the translation of specific RNA transcripts devoted to conferring growth advantages and immune protection to cancer cells. To verify this hypothesis three complementary specific Aims have been designed: Aim 1: Design, synthesize and improve small molecule inhibitors of hnRNP A18. Aim 2: Prioritize compounds through in vitro methods including RNA binding, cell reporter assay, proliferation and toxicity. Aim 3: Determine in vivo anti-tumor and ADMET properties of lead compounds, employing, xenograft, syngeneic and Patients Derived (PDX) tumors models. A multidisciplinary team of experts composed of medicinal chemists, structural biologist, theoretical chemists, cancer biologist, immunologist and an oncologist has been assembled to develop and optimize this new class of anticancer agents with the ultimate goal of bringing them into the clinic.


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 = $805,096 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	000	2	11/15/2024	NON-COMPETING CONTINUATION	$575,397
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	001	2	11/20/2024	SUPPLEMENT FOR EXPANSION	$165,766
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	002	2	6/16/2025	NON-COMPETING CONTINUATION	$63,933
														Subtotal = $805,096

Issue Date FY: 2024 ( Subtotal = $714,777 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	001	1	7/31/2024	SUPPLEMENT FOR EXPANSION	$75,447
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Cancer Treatment Research	000	1	12/11/2023	NEW	$639,330
														Subtotal = $714,777

Grand Total All Awards = $1,519,873

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First in Class Small molecules to simultaneously inhibit protein translation and an immune checkpoint in cancers

Award Number: R01CA285468

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/11/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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