Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent corre-lation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the b-catenin level, and accordingly inhibit the Wnt/b-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the poten-tial to treat TNBC.(c) 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

Triple-negative breast cancer (TNBC) is a highly malignant and poor-prognosis disease. Annexin A3 (ANXA3) is a potential prognostic biomarker with a strong correlation to poor prognosis in patients. Researchers have discovered a first-in-class ANXA3-targeted small molecule (R)-SL18, which has shown excellent anti-proliferative and anti-invasive activities in TNBC cells. (R)-SL18 directly binds to ANXA3 and increases its ubiquitination, leading to ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 demonstrates safe and effective therapeutic potency in a TNBC patient-derived xenograft model with high ANXA3 expression. Furthermore, (R)-SL18 can reduce the level of beta-catenin and inhibit the Wnt/beta-catenin signaling pathway in TNBC cells. Overall, this data suggests that targeting the degradation of ANXA3 with (R)-SL18 has the potential to be a treatment strategy for TNBC.