Date of Completion

Spring 5-1-2026

Thesis Advisor(s)

Michael Kienzler; Stacey Hanlon; Lauren Wilson; Kenneth Cormier

Honors Major

Molecular and Cell Biology

Second Honors Major

Allied Health Sciences

Third Honors Major

Individualized Major

Disciplines

Cell Biology | Chemistry | Medicinal-Pharmaceutical Chemistry | Organic Chemistry | Pharmacology

Abstract

Store-operated calcium entry (SOCE) through calcium release-activated

calcium (CRAC) channels is the dominant pathway for sustained Ca2+ influx in

non-excitable cells and is essential for T cell activation, driving downstream

signaling through the calcineurin-NFAT transcriptional axis. Dysregulation of

SOCE produces multi-systemic disease phenotypes, establishing that precise,

spatiotemporally controlled modulation of this pathway is a fundamental

therapeutic requirement. ML-9 is one of the only characterized small molecules

capable of targeting SOCE upstream at the level of STIM1 localization, but lacks

the selectivity, pharmacokinetic properties, and spatiotemporal control necessary

for therapeutic development.

This work describes the design, synthesis, and biological evaluation of two

photoswitchable ML-9 derivatives incorporating an azobenzene photoswitch into

the ML-9 homopiperazine sulfonamide scaffold. JM 1-44, (E)-1-((4-

(phenyldiazenyl)phenyl)sulfonyl)-1,4-diazapane and JM 1-30, (E)-4-((4-((1,4-

diazapan-1-yl)sulfonyl)phenyl)diazinyl)-N,N-diethylaniline. Both compounds

demonstrated dose-dependent inhibition of SOCE-driven NFAT transcriptional

activity in the Jurkat-Lucia NFAT reporter cell assay, with potencies comparable

to or exceeding that of the parent compound ML-9. Photoswitching experiments

with JM 1-44 revealed a measurable shift in inhibitory potency upon UV

irradiation, providing preliminary evidence that light can modulate the biological

activity of this compound supporting the feasibility of photopharmacological

control of STIM1-mediated SOCE.

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