Promising Non-Toxic, Anti-Inflammatory Small-molecule for Treatment of Ulcerative Colitis

Background

Over 1.5 million individuals in the United States suffer from Ulcerative colitis (UC), an inflammatory bowel disease that causes chronic inflammation in the digestive tract. Individuals diagnosed with UC experience multiple hospitalizations, high colectomy rates, high incidence of cancer, and an overall poor quality of life.

Unfortunately, there is no cure for this disease, and with an annual increase of approximately 10-12 per 100,000 individuals and a national financial burden of 30 billion dollars, there is a desperate need for an efficient treatment. Current treatments, such as biologics, small molecule inhibitors, and steroids, burden UC patients with severe side effects and long-term adverse effects due to off-target effects/toxicity, and only result in remission rates that are at best 50%.

The following invention presents a superior treatment option that aims to overcome these obstacles in treating UC.

Technology Overview

Researchers at Einstein invented a first-in-class small molecule to treat intestinal inflammation.

The work is based on the seminal discovery that intestinal microbial L-tryptophan metabolism results in specific metabolites like indole, indole propionic acid (IPA), and indole acetate. These metabolites can positively regulate intestinal barrier function (permeability and mucus integrity) in both health and disease. Thus, using microbial metabolite mimicry as a tool for drug design, the laboratory discovered hit compounds capable of targeting the PXR receptor. PXR is a well-established target for its anti-inflammatory roles in the intestines, and its activation attenuates NFkB-mediated inflammatory signals, which are required to induce a large number of inflammatory genes. Hit-to-lead studies identified FKK6, a first-in-class molecule capable of targeting PXR with anti-inflammatory properties.

Further lead optimization using mouse models and human intestinal organoids, the team successfully demonstrated selective and potent targeting of PXR by FKK6 in the intestines ( and ), with limited systemic exposure. The latter feature minimizes its off-target toxicity, ensures minimal side effects, and long-term remission, making FKK6 an ideal drug candidate. Given the large market size for intestinal inflammation (UC, IBD, Crohn’s disease), the FKK6 is a promising small molecule for treating moderate to severe disease with improved quality of life in patients.

Further Details:

• Dvorak et al., Trends in Pharm Sci (2020)
• Dvorak et al., EMBO Mol Med (2020)
• Li et al., Bioorganic Chemistry (2021)
• Dovorak et al., Bioorganic Chemistry (2024)
• Sládeková et al., J Pharmacol Exp Ther (2025)

Stage of Development

• Preclinical studies were completed in a mouse model of induced UC and human intestinal organoids

Benefits

• First-in-class molecule
• Reduced toxicity
• Steroid sparing therapy
• Long-term remission
• Improved quality of life

Applications

• Target intestinal inflammation and reduce its life-time complications
• Treatment for moderate to severe UC
• Treatment for IBD
• Treatment for Crohn’s disease

Opportunity

• Licensing opportunity
• Collaboration