# Discovery and development of potent inhibitors of Jun N-terminal kinase for non-hormonal treatment of endometriosis and associated pain

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $560,830

## Abstract

PROJECT SUMMARY
Endometriosis is an inflammatory disease affecting the peritoneal cavity that has been treated predominantly
with endocrine modulators to impose growth restriction through suppression of estrogen action. Worldwide,
there are 28 development or marketed products that address the endocrine axis of endometriosis. However,
few, if any drug discovery efforts address the non-hormonal axes of this disease as stand-alone therapy, or as
sequential therapy during hiatus from endocrine-suppressing agents. The pathophysiology shared by deep
infiltrating endometriosis, superficial peritoneal endometriosis and ovarian endometrioma includes epithelial-
mesenchymal trans-differentiation (EMT) and fibroblast-myofibrobocyte trans-differentiation. The focus of this
proposed research is to develop novel, potent, highly selective inhibitors of Jun N-terminal kinase (JNK-I) that
can interrupt trans-differentiation pathways that are the pathological basis for lesion survival.
Our preliminary results with bentamipimod (JNK-I) have validated this approach demonstrating equivalent
regression of lesions as were obtained with GnRH antagonist in primate models. Furthermore, results in
rodent, non-human primate models, and in humans (Phase II results) demonstrate regression of lesions
without impact on eutopic endometrium, or endogenous hormone levels. Our project integrates reproductive
biologists, immunologists, medicinal chemists and biomedical engineers with demonstrated leadership in
academic and pharmaceutical research to discover novel JNK-I and characterize their potential for patients.
Our program incorporates state-of-the-art technologies to help achieve our objectives. In Specific Aim 1, we
will optimize affinity and permeability of c-jun N-terminal kinase (JNK-I) obtained following two rounds of
selection from our DNA-encoded Chemistry Technology (DEC-Tec) libraries at Baylor College of Medicine
containing over 4 billion compounds. The efficacy of these compounds in vitro will be evaluated in established
cell lines and in primary human endometrial stromal cells. In Specific Aim 2, we will compare the efficacy of
novel JNK-I prepared at the Center for Drug Discovery to tanzisertib in a previously validated mouse
model of endometriosis with endometrium-specific ER? overexpression (ER?:OE) that enables
evaluation of anti-inflammatory therapies amidst elevated ER? response and compromised progesterone
sensitivity. These comparisons have never been generated for JNK-I and provide an opportunity to assess
treatment efficacy based on improved potency of JNK-I. In Specific Aim 3, we will demonstrate that
emerging diagnostics of the menstrualome can stratify patients for future JNK-I therapy based on their
ex vivo cytokine production from macrophages and NK cells obtained from menstrual effluent. The
objectives for all three Specific Aims generate new information regarding the action of JNK-I in endometriosis
for both known and novel JNK-I.

## Key facts

- **NIH application ID:** 10121889
- **Project number:** 1R01HD099341-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Stephen Sunderland Palmer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $560,830
- **Award type:** 1
- **Project period:** 2021-08-11 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10121889

## Citation

> US National Institutes of Health, RePORTER application 10121889, Discovery and development of potent inhibitors of Jun N-terminal kinase for non-hormonal treatment of endometriosis and associated pain (1R01HD099341-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10121889. Licensed CC0.

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