Friday, January 23, 2026 1/23/2026

Selective Inhibitors of T Cell Activation Target Exportin-1 at Cys528 to Suppress Pathological T Cell Activation

Award Number: R01AI171104
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: 01/23/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Selective Inhibitors of T Cell Activation Target Exportin-1 at Cys528 to Suppress Pathological T Cell Activation - ABSTRACT Multiple diseases, including graft-versus-host disease, transplant rejection, rheumatoid arthritis, and lung fibrosis are known to be driven by pathological activation of T cells. While T cell activation is a key part of many immune responses, this process can become pathological when T cells inaccurately recognize a patient’s own tissues or in the context of tissue transplantation. While immunomodulatory drugs including corticosteroids and cyclosporine are FDA-approved, these agents act on many immune cell types, leading to broad immunosuppression and severe side effects. Past high-throughput screening efforts identified and validated small molecule ‘Selective Inhibitors of T Cell Activation (SITCAs)’ that function in vitro and in vivo without influencing inflammatory responses in other cell types. While these molecules suggested the potential for novel T cell-selective immunomodulatory agents, lack of understanding of their cellular targets prevented further drug discovery efforts. Exportin-1 (XPO1) catalyzes nuclear-to-cytoplasmic transport of hundreds of proteins and also has established roles in regulating the centromere and transcription. The highly toxic natural product Leptomycin was used to establish that blocking XPO1-mediated nuclear export led to cancer cell death, and later efforts led to FDA approval of selinexor, a Selective Inhibitor of Nuclear Export (SINE), for multiple myeloma patients who have failed at least four prior therapies. Our data establish that multiple Selective Inhibitors of T Cell Activation also target XPO1, but with novel pharmacology: these ‘partial antagonists’ inhibit XPO1’s novel role in the T cell activation process but have minimal effects on nuclear export and are substantially less cytotoxic. These data suggest that XPO1 represents a promising new target for blocking pathological T cell activation, and that the novel partial antagonist profile is desirable to avoid on-target cytotoxicity associated with existing XPO1 modulators. This proposal seeks to understand and optimize XPO1 partial antagonists for application in immune- mediated diseases. First, we seek to use structural and functional assays to understand how different small molecules that bind the same site of XPO1 show such divergent effects on cellular phenotypes including nuclear export and cell viability. In Aim 2, we will establish the cellular mechanisms by which XPO1 modulators block T cell activation, with the hypothesis that dissociation from chromatin of XPO1, NFAT transcription factors, and other chromatin factors plays a central role. Finally, we will use medicinal chemistry to optimize the partial antagonist profile and evaluate leading partial antagonists in preclinical models of T cell function, including using human primary T cells and in a mouse model of lung fibrosis in which T cells are known to play a role. Together these studies will extend XPO1 as a therapeutic beyond late-stage cancer patients by optimizing novel partial antagonists of XPO1.


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 = $508,611 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	4	1/12/2026	NON-COMPETING CONTINUATION	$508,611
														Subtotal = $508,611

Issue Date FY: 2025 ( Subtotal = $498,038 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	3	12/18/2024	NON-COMPETING CONTINUATION	$498,038
														Subtotal = $498,038

Issue Date FY: 2024 ( Subtotal = $518,271 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	2	12/14/2023	NON-COMPETING CONTINUATION	$466,445
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	001	2	5/20/2024	NON-COMPETING CONTINUATION	$51,826
														Subtotal = $518,271

Issue Date FY: 2023 ( Subtotal = $510,221 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Allergy and Infectious Diseases Research	000	1	1/23/2023	NEW	$510,221
														Subtotal = $510,221

Grand Total All Awards = $2,035,141

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Selective Inhibitors of T Cell Activation Target Exportin-1 at Cys528 to Suppress Pathological T Cell Activation

Award Number: R01AI171104

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: 01/23/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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