# Identification of TR4 Modulators for Treatment of Cushing Disease.

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $401,115

## Abstract

ABSTRACT
 Cushing Disease (CD) is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor
that causes excess adrenal-derived cortisol. It is a life-threatening “orphan disease” with a staggering annual
health care cost that is >7-fold higher than average patients. Surgical removal is the current first-line therapy but
the disease frequently recurs. Repeat surgery, radiation therapy and bilateral adrenalectomy are not always
successful and associated with major morbidity. Currently available drugs or those in clinical trials for CD do not
target the pituitary corticotroph tumor itself and escape from control is common with long-term use. A clear unmet
need for efficacious and safe therapies that offer biochemical and tumor control exists. We hypothesize that
direct targeting of corticotroph tumors to modulate ACTH and in turn, glucocorticoid secretion is the optimal way
to treat CD. We recently demonstrated that the orphan testicular receptor 4 (TR4, also known as NR2C2) is a
potent regulator of hypothalamic-pituitary-adrenal (HPA) axis function and directly regulates pro-
opiomelanocortin (POMC) gene transcription and ACTH secretion. We hypothesize that small molecule inhibitors
of TR4 action would be potent inhibitors of corticotroph tumor hormone (ACTH) secretion. Such a discovery
would be a transformative therapy for Cushing disease as no similar therapies exist. To identify and characterize
TR4 small molecule modulators, we will perform a large scale small molecule library screen using our unique
series of transactivation assays that include a TR4-directed GAL4-LBD system and POMC-promoter reporters
as well as a secondary screen in human corticotroph tumor primary cultures. Our first aim will use a mammalian
one-hybrid GAL4-LBD system to identify TR4 modulators from a library of 200,000 distinct compounds. Potential
“hit” compounds will be confirmed by dose-response evaluation assays to calculate their EC50. Compounds
identified in aim 1 will be further validated in aim 2 using a POMC transactivation assay using full-length and
truncated TR4 variant plasmids together with a series of POMC promoter-driven luciferase reporters in murine
corticotroph tumor AtT20 cells. A secondary screen will also be performed in human corticotroph tumor primary
cultures to confirm their in vitro effects on ACTH secretion. We expect our proposal will identify and rigorously
validate compounds that efficiently and specifically abrogate TR4 actions to inhibit ACTH secretion and lead to
the discovery of safe and efficacious lead TR4 inhibitory compounds that can be further advanced as potential
drug therapies for CD.

## Key facts

- **NIH application ID:** 10199436
- **Project number:** 1R21CA259943-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** ANTHONY P HEANEY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $401,115
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199436

## Citation

> US National Institutes of Health, RePORTER application 10199436, Identification of TR4 Modulators for Treatment of Cushing Disease. (1R21CA259943-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10199436. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*