Endometriosis Inspires Re-Examination of Known Targets

Author: Liz Jones
Reviewers: Matt Hesse, Wendy Young
Editor: Julia Clay

Highlights

Endometriosis is a debilitating chronic inflammatory disease that affects an estimated 10% of women in their reproductive years, but which remains under-researched and under-funded
At the 2026 HERS meeting, preclinical programs evaluating FP antagonists, LFA-1 antagonists, and CB1/2 partial agonists were all shown to have encouraging efficacy in mouse models of endometriosis
AI-driven platforms were used to identify potential previously known (FP, CB2) and novel (GPB2, HCK) targets for endometriosis.

The Untapped Potential of Endometriosis Drug Development

Endometriosis is an under-diagnosed, under-researched, and underfunded disease—one whose large patient pool is without adequate treatments, leaving significant untapped therapeutic and fiscal potential on the table. In 2022, 6.5 million American women were diagnosed with endometriosis, representing ~2% of the US population—in contrast, the disease received just 0.038% ($16 M) of NIH grant funding that year. This under-resourcing is even more problematic because there are no non-hormonal disease-modifying therapies, and in fact a clear, unified understanding of disease pathogenesis remains elusive. Currently, management of endometriosis symptoms typically consists of a combination of analgesics/anti-inflammatories such as NSAIDs (nonsteroidal anti-inflammatory drugs) and hormonal therapies like GnRH (gonadotropin-releasing hormone) antagonists, or oral contraceptives to suppress ovarian estrogen production. This small arsenal of treatments approved for endometriosis is limited to symptom management, targeting the pain or inflammation associated with the disease, without addressing the underlying pathology. To meet the moment and deliver impactful novel therapies, a community investment in enhanced disease understanding is essential.

Elucidating Causal Pathways of a Multi-Factor, Heterogenous Disease

Endometriosis is a chronic inflammatory condition that causes painful growths of endometrial tissue outside the uterus. Beyond the severe impacts of this pain on a patient’s quality of life, endometriosis is one of the leading causes of female infertility and carries a 50% increased risk of cervical cancer. The rate and severity of lesion growth is extremely heterogeneous among patients, one of several factors that obscure the underlying biology. Lesion formation occurs through a combination of implantation and growth of new tissue outside the uterus, however, a consensus has not been reached on either the source of the migratory tissue or the mechanistic factors leading to its ex-utero growth. Disease progression is influenced by many factors, including a combination of estrogen fluctuation, activation of fibrotic pathways, and inflammatory and immune responses (Figure 1). The multifaceted nature of the disease, without an identified genetic driver, makes deconvoluting contributing biological pathways challenging.

Revisiting Targets as a Therapeutic Approach

The proven involvement of inflammatory, immunological, and fibrotic signaling in endometriosis presents opportunities to borrow knowledge, targets and compounds from long-established research into other diseases. Target and drug repurposing (as discussed in a recent Drug Hunter review) are strategies that take chemical tools developed for a well-characterized target/indication and apply them to other diseases, leveraging existing knowledge of the target’s druggability. Even though endometriosis has many non-specific symptoms and lacks robust, established biomarkers, rational drug/target repurposing approaches are on the rise for the disease, in the hope of identifying potential symptom- and disease-modifying therapies for endometriosis.

Target Repurposing: Highlights from the Inaugural HERS Summit

The role of target repurposing as an approach for tackling endometriosis in the absence of widespread bespoke drug development programs was highlighted in several presentations at the HERS (Health Executive & Research Summit) conference in San Diego in March 2026 (Table 1).

FP Antagonists: Moving Down the Prostaglandin Pathway to Suppress Contraction-Based Symptoms

The fibrotic nature of lesions has been increasingly understood as a key part of disease pathology and is hypothesized to play a role in the dysmenorrhea (severe menstrual pain) typical of endometriosis. The severity of dysmenorrhea has been correlated with the frequency of uterine contractions, which are typically higher in endometriosis patients, regardless of menstrual cycle phase. The prostaglandin PGF2⍺ is a well-characterized driver of uterine contractions and associated dysmenorrhea, and PGF2⍺ levels in menstrual fluid have been correlated to patient-reported pain intensity. PGF2⍺ signaling is a driver of fibrosis in diseases such as idiopathic pulmonary fibrosis (Figure 2).

Leveraging the established roles of PGF2⍺ signaling in fibrosis and uterine contractions, Maipl Therapeutics is currently evaluating antagonists of the target receptor of PGF2⍺, FP (prostaglandin F receptor), as potential endometrial therapies. In contrast to NSAIDs, FP antagonists can offer targeted prostaglandin pathway modulation by acting further downstream in the pathway, potentially minimizing side effects associated with non-selective NSAIDS. Maipl’s Aritro Sen shared the progress of this program, built on FP antagonists licensed from Ferring Pharmaceuticals, detailing their evaluation in a battery of preclinical, IND-enabling studies.

While the structure of their lead compound in this program, MA-4604, is undisclosed, Ferring Pharmaceuticals holds two small molecule patent applications for FP antagonists (WO2025168353A1, WO2025168354A1, Figure 3). These IP disclosures include compound binding data to FP and to EP4, a receptor for prostaglandin E, as a measure of family-level receptor selectivity. Several compounds hold sub-nM affinity for FP (TGI-09 hFP K_b = 0.63 nM) and >100-fold selectivity. Although detailed study data was not disclosed, Sen shared that MA-3604 performs well in models of uterine contractility (e.g., a rat intra-uterine pressure model), PGF2⍺-induced acute pain, and also in a mouse endometriosis model—setting the stage for a first-in-human clinical trial projected to begin in 2027.

CB2 Partial Agonists: Activating the ECS for Endometriosis Treatment

Nalu Bio is taking an AI-driven approach to target discovery in endometriosis. The company’s expertise is in the ECS (endocannabinoid system). Its generative AI platform is trained on 25 ECS receptors and their interaction with ~90,000 training compounds, which is being used to engineer novel binders for targets of interest. The GPCR CB2 (cannabinoid receptor 2) is a component of the ECS that is localized to immune cells, and it modulates inflammation and tissue remodeling. CB2 was a highly studied drug discovery target in the early 2000s, and selective CB2 agonists have been tested clinically in rheumatoid arthritis, inflammatory bowel disease, and neuroinflammation in Alzheimer’s disease. However, clinical translation of this biology proved challenging, and the FDA has yet to approve a CB2 agonist drug.

Nalu Bio has leveraged their platform to engineer synthetic cannabinoid partial agonists targeting CB2 and the related receptor CB1 for endometriosis. The lead compound, NALU-0016-3, is a dual CB2/CB1 partial agonist with biased G-protein signaling; the partial CB1 agonism is expected to deliver sustained analgesia, while the CB2 activity drives immune modulation, lesion inhibition and restoration of tissue homeostasis. Preclinically, NALU-0016-3 delivers short-term pain reductions comparable to morphine in a latency mouse model (Figure 4) and “NSAID-level efficacy” in a mouse endometriosis model, with statistically significant reductions in lesion volumes compared with vehicle—supporting the compound’s potential for disease modification.

LFA-1 Antagonist: From Dry Eye Disease to Endometrial Inflammation

Recognizing the economic and healthcare opportunities for novel endometriosis treatments, Insilico Medicine has developed AI-driven target-ID workflows to discover causal targets of endometriosis—a discovery program shared by Insilico’s Petrina Kamya at the 2026 HERS. Using the PandaOmics platform, the team used AI and bioinformatic approaches to process biomedical data of endometriosis patients and matched controls to compile a list of ranked candidate targets belonging to a known druggable protein class for in vitro validation. These efforts culminated in the identification of three promising targets, one of which has an FDA-approved drug: ITGB2 (integrin beta 2), a subunit of integrin LFA-1 (lymphocyte function-associated antigen-1), the antagonist of which, lifitegrast, is FDA-approved for dry eye indications.

Integrins are heterodimeric transmembrane proteins, essential in leukocyte adhesion and migration in immune responses. Integin-based immune synapse disruption is a clinically validated strategy for dampening dysregulated immune responses, and it represents a compelling target in endometriosis. Insilico found that ITGB2 was significantly upregulated in endometriosis samples—nine different Reactome database-annotated pathways associated with immune response and inflammation were also upregulated with ITGB2.

These results make the FDA-approved LFA-1 antagonist lifitegrast (Xiidra®) a potential endometriosis therapy. Lifitegrast is a competitive binder of the LFA-1 αL subunit and prevents LFA-1 binding its ligand, ICAM-1 (intercellular adhesion molecule 1). In a mouse model of endometriosis, lifitegrast reduces lesion volume and weight, as well as lowering ITGB2 expression when systemically administered at 0.50 and 0.75 mg/kg doses (Figure 6).

Lifitegrast’s origin as an ophthalmic solution (Xiidra® for dry eye disease) means that the path to an endometriosis indication will require significant effort to transform it into an oral medication. While there are no examples of oral LFA-1 antagonists that have progressed into clinical development, the validation of this target in inflammation—and Insilico’s data linking it to endometriosis—hopefully makes these challenges worthy of investment.

Insilico Identified Novel Putative Endometriosis Targets

Insilico Medicine has also disclosed two other novel targets for endometriosis that have promising preclinical results, and which were identified through the same PandaOmics-driven pipeline as ITGB2/LFA-1.

GBP2 (guanylate binding protein 2) is an interferon-inducible part of orchestrated innate immune responses. It has been proposed as a potential biomarker for several cancers based on its association with immunotherapeutic responses.
Hck (hemopoietic cell kinase) is a member of the Src kinase family and mediates immune function. It also has been suggested as a biomarker to track immune cell infiltration in diseases involving myeloid and B-lymphocyte cells.

Both proteins show elevated expression in human endometrial tissue when compared ex vivo to normal tissue, while in cell cultures siRNA knockdown of either protein led to a reversal of endometriotic phenotypes (decreased proliferation, increased apoptosis induction). These results were further confirmed in an in vivo endometriosis animal model, where their knockdown led to suppression of endometriotic lesion growth compared to control. As novel targets, biology work is currently ongoing to evaluate the safety profiles of GBP2/HCK inhibition before a discovery campaign can begin.

Stepping Back: Repurposing Has Much to Offer, But Ultimately Novel Targets and Drugs Are Needed for Transformative Progress

These programs represent genuine progress towards identifying new targets for endometriosis and will hopefully lead to the development of clinical candidates in this grossly underserved disease. By repurposing established targets from other inflammatory diseases, these programs have undergone a shortened discovery process. However, while repurposing of targets and drugs has a place in drug discovery, it cannot be the singular stopgap to address the critical unmet needs of this patient population. When asked about the place for repurposing in endometriosis drug discovery, 2026 HERS chair and Drug Hunter’s SAB Board Chair, Wendy Young, said this:

"Drug repurposing remains a powerful strategy to connect existing, approved medicines with new biological insights and unmet medical needs. While it offers a faster, proven path to patients, it often delivers incremental progress rather than true transformation. In endometriosis—and many other conditions—what we urgently need are bold, mechanism-driven therapies targeting novel, unproven pathways, coupled with the conviction to see these innovations through."

Endometriosis Inspires Re-Examination of Known Targets at the Inaugural HERS Meeting