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Targeting RIPK3 in Flu-Associated Lung Injury

Award Number: R01AI144400
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/18/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Targeting RIPK3 in Flu-Associated Lung Injury - PROJECT SUMMARY/ABSTRACT Seasonal influenza A virus (IAV) infections account for over 700,000 hospitalizations and 50,000 annual deaths in the US alone. Moreover, highly virulent H5 and H7 strains of avian IAV, while currently limited in their spread between humans, are only a few mutations from acquiring the capacity for widespread transmissibility. As current vaccines and antiviral strategies are either limited in their efficacy or susceptible to viral resistance and evasion, identifying new therapeutic entry-points for seasonal and virulent IAV disease, preferably those that target pathogenic host signaling pathways, is an urgent imperative. We have identified the host kinase RIPK3 as a promising new entry point for therapeutic development against IAV. RIPK3 is the central mediator of a highly pro-inflammatory form of cell death termed necroptosis, which we have found is a major contributor to lung injury and inflammation during IAV infection. Both seasonal and pandemic strains of IAV trigger RIPK3- dependent necrotic lung damage that we propose underlies Acute Respiratory Distress Syndrome (ARDS), as well as viral and bacterial pneumonia, each of which remain major causes of morbidity and mortality following IAV infection. Notably, RIPK3 also mediates or amplifies a range of chronic TNF-α-mediated pathologies (such as rheumatoid arthritis) making it a very attractive new molecular target for multiple inflammatory conditions. Curiously, given how important a therapeutic target RIPK3 potentially is, no selective RIPK3 inhibitors have been advanced into clinical trials. We now have developed a new structural class of RIPK3 inhibitor, which we call the UH15 series, and which is based on a pyrido[2,3-d]pyrimidine scaffold that targets both the ATP- as well as the allosteric Glu-out pockets of RIPK3. Our preliminary findings reveal that UH15 analogs, after just one round of optimization, are already more potent than current RIPK3 inhibitors and display promising activity against IAV induced necrosis in vitro and in vivo. These exciting results highlight the immediate translational potential of the UH15 series for necrotic lung injury and consequent ARDS and pneumonia triggered by seasonal and virulent strains of IAV. The goals of our proposal are to iteratively optimize UH15-based compounds for RIPK3 blockade in vitro and, by use of a rapid mouse model of RIPK3-mediated pathology (the TNF SIRS model), prioritize compounds for use in vivo (Aim 1). We then propose to assess these UH15 compounds for therapeutic efficacy in a variety of IAV-triggered disease settings, including the scenarios of (1) high-risk seasonal IAV infections, (2) infection by highly pathogenic avian IAV, and (3) secondary pneumococcal pneumonia following seasonal IAV infection (Aim 2). The proposed studies bring together a team of researchers with strong, complementary expertise in small-molecule medicinal chemistry (Cuny), RIPK3 kinase biochemistry and function in inflammation (Degterev), and RIPK3-mediated cell death signaling during IAV pathogenesis (Balachandran, Thomas). Successful completion of these Aims has the potential to transform the treatment of multiple IAV-induced diseases initiated or amplified by necrotic lung injury.


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: 2026 ( Subtotal = $0 )
2026	2023	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	1/27/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $702,005 )
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	8/2/2023	NON-COMPETING CONTINUATION	$702,005
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	5	9/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $702,005

Issue Date FY: 2022 ( Subtotal = $731,691 )
2022	2022	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	8/23/2022	NON-COMPETING CONTINUATION	$731,691
														Subtotal = $731,691

Issue Date FY: 2021 ( Subtotal = $789,265 )
2021	2021	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	8/17/2021	NON-COMPETING CONTINUATION	$789,265
														Subtotal = $789,265

Issue Date FY: 2020 ( Subtotal = $678,878 )
2020	2020	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	8/13/2020	NON-COMPETING CONTINUATION	$678,878
														Subtotal = $678,878

Issue Date FY: 2019 ( Subtotal = $719,078 )
2019	2019	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	9/18/2019	NEW	$719,078
														Subtotal = $719,078

Grand Total All Awards = $3,620,917

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Targeting RIPK3 in Flu-Associated Lung Injury

Award Number: R01AI144400

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/18/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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