Kopparapu Prasad R, Löhr Christiane V, Pearce Martin C, Tyavanagimatt Shanthakumar, Nakshatri Harikrishna, Kolluri Siva K
Cancer Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331-8580, United States.
Department of Biomedical Sciences, Carlson College of Veterinary Medicine, Oregon State University, Corvallis, Oregon 97331-4801, United States.
ACS Pharmacol Transl Sci. 2024 May 1;7(5):1302-1309. doi: 10.1021/acsptsci.3c00360. eCollection 2024 May 10.
The B-cell lymphoma-2 (Bcl-2) family of proteins plays a vital role in tumorigenesis. Cancer cells utilize the expression of Bcl-2 to evade therapy and develop resistance. Bcl-2 overexpression also causes cancer cells to be more invasive and metastatic. About 80% of cancer deaths are due to metastases, and yet targeted therapies for metastatic cancers are scarce. We discovered a small molecule, BFC1103, which changes the conformation of Bcl-2 to convert the antiapoptotic protein to a proapoptotic protein. BFC1103-induced apoptosis is dependent on the expression levels of Bcl-2, with higher levels causing more apoptosis. BFC1103 suppressed the growth of breast cancer lung metastasis. BFC1103 has the potential for further optimization and development for clinical testing in metastatic cancers that express Bcl-2. This study demonstrates a new approach to target Bcl-2 using a small molecule, BFC1103, to suppress metastatic disease.
B细胞淋巴瘤-2（Bcl-2）蛋白家族在肿瘤发生过程中起着至关重要的作用。癌细胞利用Bcl-2的表达来逃避治疗并产生耐药性。Bcl-2的过度表达还会使癌细胞更具侵袭性和转移性。约80%的癌症死亡是由转移所致，然而针对转移性癌症的靶向治疗却很匮乏。我们发现了一种小分子BFC1103，它能改变Bcl-2的构象，将抗凋亡蛋白转变为促凋亡蛋白。BFC1103诱导的细胞凋亡依赖于Bcl-2的表达水平，表达水平越高，凋亡越多。BFC1103抑制了乳腺癌肺转移的生长。BFC1103有进一步优化和开发的潜力，可用于对表达Bcl-2的转移性癌症进行临床试验。本研究展示了一种利用小分子BFC1103靶向Bcl-2以抑制转移性疾病的新方法。
