Characterizing selective inhibitors of transcriptional activity as therapeutics for pathological t cell activation

The National Institute of Allergy and Infectious Diseases awarded Case Western Reserve University $110,228 on November 23, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to characterize selective inhibitors of transcriptional activation (SITAs) as therapeutics for pathological T cell activation.

The research investigates the mechanism by which SITAs—novel molecules that covalently bind to exportin-1 (XPO1) at the C528 position—inhibit T cell activation despite binding to the same pocket as selective inhibitors of nuclear export (SINEs), which suppress nuclear export rather than T cell activation. The project tests the hypothesis that SITAs' phenotypic divergence from SINEs stems from rapid reversion of the covalent bond formed in the C528 pocket. This work addresses autoimmune disorder treatment by developing targeted inhibitors that avoid the systemic immunosuppression side effects of global immune suppressants currently used to treat millions of annually diagnosed autoimmune patients.

Performance will occur in Cleveland, Ohio, with an ultimate completion date of May 25, 2030. The award is classified as a Project Grant.

Abstract

Annually, millions of patients are diagnosed with autoimmune disorders. The majority of these are treated with global immune suppressants. These drugs often tip the balance from autoimmunity to immune suppression, triggering undesirable, systemic side effects. Previously, IT had been established in literature that exportin-1 (XPO1) is a novel target for the inhibition of t cell activation. XPO1 is canonically recognized as a nuclear cargo export protein where IT shuttles cargo from the nucleus into the cytoplasm. Recently, IT has been reported that XPO1 also plays a critical role as a chromatin factor. XPO1's chromatin function can be inhibited with novel molecules coined "selective inhibitors of transcriptional activation" (sitas). Mechanistically, IT has been determined that these sitas covalently bind to the C528 position of XPO1 in the same binding pocket as known nuclear export inhibitors called "selective inhibitors of nuclear export" (sines), as exemplified by the FDA approved inhibitor, selinexor. While sitas and sines covalently engage the same pocket, IT is mechanistically unclear how and why these reported sitas have the disparate phenotypic effect of inhibiting t cell activation compared to established sines which inhibit nuclear export. This proposal seeks to test the central hypothesis that the sitas' phenotypic deviation from sines stems from the rapid reversion of the covalent bond formed by sitas in the C528 pocket.