Department of Biological Chemistry, University of California Irvine, Irvine, CA 92697, USA.
Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093, USA.
Biomolecules. 2024 Aug 8;14(8):967. doi: 10.3390/biom14080967.
p53 is a crucial tumor suppressor in vertebrates that is frequently mutated in human cancers. Most mutations are missense mutations that render p53 inactive in suppressing tumor initiation and progression. Developing small-molecule drugs to convert mutant p53 into an active, wild-type-like conformation is a significant focus for personalized cancer therapy. Prior research indicates that reactivating p53 suppresses cancer cell proliferation and tumor growth in animal models. Early clinical evidence with a compound selectively targeting p53 mutants with substitutions of tyrosine 220 suggests potential therapeutic benefits of reactivating p53 in patients. This study identifies and examines the UCI-1001 compound series as a potential corrector for several p53 mutations. The findings indicate that UCI-1001 treatment in p53 mutant cancer cell lines inhibits growth and reinstates wild-type p53 activities, including DNA binding, target gene activation, and induction of cell death. Cellular thermal shift assays, conformation-specific immunofluorescence staining, and differential scanning fluorometry suggest that UCI-1001 interacts with and alters the conformation of mutant p53 in cancer cells. These initial results identify pyrimidine trione derivatives of the UCI-1001 series as candidates for p53 corrector drug development.
p53 是脊椎动物中一种重要的肿瘤抑制因子，其在人类癌症中经常发生突变。大多数突变是错义突变，使 p53 无法抑制肿瘤的起始和进展。开发将突变型 p53 转化为具有野生型样构象的小分子药物是个性化癌症治疗的一个重要焦点。先前的研究表明，重新激活 p53 可抑制动物模型中的癌细胞增殖和肿瘤生长。具有靶向突变型 p53 中酪氨酸 220 取代的化合物的早期临床证据表明，重新激活 p53 可能对患者有治疗益处。本研究确定并研究了 UCI-1001 化合物系列作为几种 p53 突变的潜在校正剂。研究结果表明，UCI-1001 处理 p53 突变型癌细胞系可抑制生长并恢复野生型 p53 活性，包括 DNA 结合、靶基因激活和诱导细胞死亡。细胞热转移分析、构象特异性免疫荧光染色和差示扫描荧光法表明，UCI-1001 与癌细胞中的突变型 p53 相互作用并改变其构象。这些初步结果确定 UCI-1001 系列的嘧啶三酮衍生物是 p53 校正药物开发的候选药物。
