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

> **NIH AI R01** · CASE WESTERN RESERVE UNIVERSITY · 2026 · $508,611

## Abstract

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 XP

## Key facts

- **NIH application ID:** 11249233
- **Project number:** 5R01AI171104-04
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Drew James Adams
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** AI
- **Fiscal year:** 2026
- **Award amount:** $508,611
- **Award type:** 5
- **Project period:** 2023-01-23T00:00:00 → 2027-12-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11249233

## Citation

> US National Institutes of Health, RePORTER application 11249233, Selective Inhibitors of T Cell Activation Target Exportin-1 at Cys528 to Suppress Pathological T Cell Activation (5R01AI171104-04). Retrieved via AI Analytics 2026-05-18 from https://api.ai-analytics.org/grant/nih/11249233. Licensed CC0.

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