8z61
Human beta-catenin crystal structure
Structural highlights
DiseaseCTNB1_HUMAN Defects in CTNNB1 are associated with colorectal cancer (CRC) [MIM:114500. Note=Activating mutations in CTNNB1 have oncogenic activity resulting in tumor development. Somatic mutations are found in various tumor types, including colon cancers, ovarian and prostate carcinomas, hepatoblastoma (HB), hepatocellular carcinoma (HCC). HBs are malignant embryonal tumors mainly affecting young children in the first three years of life. Defects in CTNNB1 are a cause of pilomatrixoma (PTR) [MIM:132600; a common benign skin tumor.[1] [2] [3] Defects in CTNNB1 are a cause of medulloblastoma (MDB) [MIM:155255. MDB is a malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children.[4] [5] Defects in CTNNB1 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000. Ovarian cancer common malignancy originating from ovarian tissue. Although many histologic types of ovarian neoplasms have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Note=A chromosomal aberration involving CTNNB1 is found in salivary gland pleiomorphic adenomas, the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1. Defects in CTNNB1 may be a cause of mesothelioma malignant (MESOM) [MIM:156240. An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle-shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos.[6] FunctionCTNB1_HUMAN Key downstream component of the canonical Wnt signaling pathway. In the absence of Wnt, forms a complex with AXIN1, AXIN2, APC, CSNK1A1 and GSK3B that promotes phosphorylation on N-terminal Ser and Thr residues and ubiquitination of CTNNB1 via BTRC and its subsequent degradation by the proteasome. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. Involved in the regulation of cell adhesion. Acts as a negative regulator of centrosome cohesion. Involved in the CDK2/PTPN6/CTNNB1/CEACAM1 pathway of insulin internalization. Blocks anoikis of malignant kidney and intestinal epithelial cells and promotes their anchorage-independent growth by down-regulating DAPK2.[7] [8] [9] [10] Publication Abstract from PubMedAberrant activation of the Wnt/beta-catenin signaling is associated with tumor development, and blocking beta-catenin/BCL9 is a novel strategy for oncogenic Wnt/beta-catenin signaling. Herein, we presented two novel beta-catenin variations and exposed conformational dynamics in several beta-catenin crystal structures at the BCL9 binding site. Furthermore, we identified a class of novel urea-containing compounds targeting beta-catenin/BCL9 interaction. Notably, the binding modalities of inhibitors were greatly affected by the conformational dynamics of beta-catenin. Among them, 28 had a strong affinity for beta-catenin (K(d) = 82 nM), the most potent inhibitor reported. In addition, 13 and 35 not only activate T cells but also promote the antigen presentation of cDC1, showing robust antitumor efficacy in the CT26 model. Collectively, our study demonstrated a series of potent small-molecule inhibitors targeting beta-catenin/BCL9, which can enhance antigen presentation and activate cDC1 cells, delivering a potential strategy for boosting innate and adaptive immunity to overcome immunotherapy resistance. Discovery of Novel 1-Phenylpiperidine Urea-Containing Derivatives Inhibiting beta-Catenin/BCL9 Interaction and Exerting Antitumor Efficacy through the Activation of Antigen Presentation of cDC1 Cells.,Zhu W, Liu C, Xi K, Li A, Shen LA, Li Y, Jia M, He Y, Chen G, Liu C, Chen Y, Chen K, Sun F, Zhang D, Duan C, Wang H, Wang D, Zhao Y, Meng X, Zhu D J Med Chem. 2024 Jun 24. doi: 10.1021/acs.jmedchem.3c02079. PMID:38912577[11] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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