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Identification of Hypoxia-Inducible Factor-2alpha Activators for Chronic Kidney Disease Anemia

Award Number: R01DK118297
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Anemia is a common and significant complication of chronic kidney disease (CKD), leading to multiple adverse consequences including, increased hospitalizations and mortality, cardiovascular disease, cognitive impairment, and diminished quality of life. Nearly half of all patients with stage 3-5 CKD experience anemia. In these patients, the underlying cause is from the diminished kidney production of erythropoietin (EPO). EPO is a glycoprotein cytokine secreted by the kidney in response to low oxygen stress to stimulate red blood cell production in the bone marrow. The hypoxia-inducible factor-2 alpha (HIF-2¿) forms heterodimer with aryl hydrocarbon receptor nuclear translocator (ARNT) to form a productive transcription factor that drives physiological EPO expression by binding to the hypoxia response element (HRE) upstream of the EPO gene. Our detailed structural elucidation of the multi-domain heterodimeric complex of HIF-2¿/ARNT has allowed Certain small-molecules such as PT2385 and OX3 can act as inhibitors of HIF-2¿ by disrupting the HIF-2¿/ARNT heterodimer. We hypothesize that other small-molecules can be identified to stabilize the HIF-2¿/ARNT heterodimer and act as activators. However, no attempts have yet been undertaken to identify HIF-2¿ activators. Driven by our recent crystallographic discovery of multiple ligand-binding cavities within this heterodimer, we designed and conducted small pilot screens based on a sensitive biochemical protein-protein interaction assay. These efforts allowed the identification of small- molecules that biochemically stabilize the HIF-2¿/ARNT heterodimer and led to enhanced EPO expression within cells. In response to new appreciation for its drug-binding potentials. NIDDK PA-16-374, we now propose to conduct a comprehensive high-throughput screen using a 350,000-compound library, together with the suite of secondary and tertiary confirmatory assays to identify HIF-2¿/-ARNT selective activators for preclinical development. These activators will have substantial advantages over the current treatments involving recombinant EPO injections, and should be significantly safer and more effective than the prolyl-hydroxylase inhibitors undergoing development.


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: 2021 ( Subtotal = $371,548 )
2021	2021	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE			GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	3/30/2021	NON-COMPETING CONTINUATION	$371,548
														Subtotal = $371,548

Issue Date FY: 2020 ( Subtotal = $351,478 )
2020	2020	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	3/26/2020	NON-COMPETING CONTINUATION	$351,478
														Subtotal = $351,478

Issue Date FY: 2019 ( Subtotal = $152,226 )
2019	2019	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	3	4/4/2019	NON-COMPETING CONTINUATION	$411,526
2019	2018	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	2	3/13/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$20,955
2019	2018	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE	OX1 2JD		GBR	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	2/15/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$321,890
2019	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/14/2019	NEW	-$581,190
2019	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	3/13/2019	NEW	-$20,955
														Subtotal = $152,226

Issue Date FY: 2018 ( Subtotal = $693,795 )
2018	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/15/2018	NEW	$693,795
														Subtotal = $693,795

Grand Total All Awards = $1,569,047

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Identification of Hypoxia-Inducible Factor-2alpha Activators for Chronic Kidney Disease Anemia

Award Number: R01DK118297

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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