Development of ARIH1 inhibitors as a novel targeted therapy in cancer

The National Cancer Institute awarded $400,000 to Toomer Therapeutics, Inc. on September 2, 2026, under the Cancer Treatment Research program (CFDA 93.395) to develop small-molecule inhibitors of the E3 ubiquitin ligase ARIH1 as a targeted therapy for triple-negative breast cancer and other cancers.

The project focuses on lead compound optimization, absorption-distribution-metabolism-excretion and pharmacokinetic studies to generate drug-like ARIH1 inhibitors, and preclinical efficacy studies of lead compounds combined with standard chemotherapy using mouse models of triple-negative breast cancer. The recipient has identified hit compounds and derivatives that inhibit ARIH1 ubiquitination in vitro, suppress cancer stemness, and increase chemotherapy sensitivity. The work is supported by data showing elevated ARIH1 levels in triple-negative breast cancer tissue correlate with reduced relapse-free and overall survival, and that ARIH1 silencing blocks epithelial-mesenchymal transition, cancer stemness, and tumor progression in preclinical models.

This is a Small Business Technology Transfer Phase I grant. The award obligates $400,000 with a period of performance through August 31, 2027. Work is performed in Charleston, South Carolina.

Abstract

Anthracycline, alkylator and taxane-based chemotherapy is the standard of care in metastatic triple negative breast cancer (TNBC). This treatment strategy results in low rates of complete pathological response and the development of recurrent disease; therefore, there is an urgent need for novel targeted therapies that can improve patient outcomes. We have delineated a novel role for the E3 ubiquitin ligase ARIH1 in tumor initiation and metastatic progression of TNBC. In BC patient data, ARIH1 levels are higher in TNBC compared to normal tissue and high ARIH1 levels are associated with reduced relapse free survival & overall survival in TNBC patients. Silencing of ARIH1 inhibits EMT and cancer stemness, linked to tumor initiation and metastatic progression, and blocks tumor progression in mouse models of TNBC. In addition, ARIH1 silenced TNBC cells are more sensitive to cell killing by chemotherapeutics commonly used for the treatment of this cancer subtype. Based on these findings, we aim to develop inhibitors of ARIH1 function as a novel therapeutic strategy in TNBC and other cancers. We have identified small molecule inhibitors of ARIH1 using molecular docking studies to search for compounds that can inhibit ARIH1 activity. HIT compounds and derivatives of the lead compound A3 can inhibit ARIH1 ubiquitination in vitro and, like ARIH1 silencing, can inhibit cancer stemness and increase chemotherapy sensitivity. The objectives of this proposal are to perform I) lead compound optimization and II) adme-PK studies to generate a more drug-like compound, followed by III) efficacy studies of lead compounds combined with chemotherapy using a mouse model of TNBC. Sttr phase I funding will achieve the major milestone of preclinical efficacy studies of lead compounds. We anticipate that the completion of this milestone will support the submission of a competitive sttr phase II proposal, focusing on IND-enabling studies, including preclinical and non-clinical safety toxicity studies. Based on our preliminary data, and on the continuing need for effective therapies for metastatic breast cancer, the compounds we have discovered show great potential for development and commercialization.