RRC ID 51942
著者 Barile E, Marconi GD, De SK, Baggio C, Gambini L, Salem AF, Kashyap MK, Castro JE, Kipps TJ, Pellecchia M.
タイトル hBfl-1/hNOXA Interaction Studies Provide New Insights on the Role of Bfl-1 in Cancer Cell Resistance and for the Design of Novel Anticancer Agents.
ジャーナル ACS Chem Biol
Abstract Upregulation of antiapoptotic Bcl-2 proteins in certain tumors confers cancer cell resistance to chemotherapy or radiations. Members of the antiapoptotic Bcl-2 proteins, including Bcl-2, Mcl-1, Bcl-xL, Bcl-w, and Bfl-1, inhibit apoptosis by selectively binding to conserved α-helical regions, named BH3 domains, of pro-apoptotic proteins such as Bim, tBid, Bad, or NOXA. Five antiapoptotic proteins have been identified that interact with various selectivity with BH3 containing pro-apoptotic counterparts. Cancer cells present various and variable levels of these proteins, making the design of effective apoptosis based therapeutics challenging. Recently, BH3 profiling was introduced as a method to classify cancer cells based on their ability to resist apoptosis following exposure to selected BH3 peptides. However, these studies were based on binding affinities measured with model BH3 peptides and Bcl-2-proteins taken from mouse sequences. While the majority of these interactions are conserved between mice and humans, we found surprisingly that human NOXA binds to human Bfl-1 potently and covalently via conserved Cys residues, with over 2 orders of magnitude increased affinity over hMcl-1. Our data suggest that some assumptions of the original BH3 profiling need to be revisited and that perhaps further targeting efforts should be redirected toward Bfl-1, for which no suitable specific inhibitors or pharmacological tools have been reported. In this regard, we also describe the initial design and characterizations of novel covalent BH3-based agents that potently target Bfl-1. These molecules could provide a novel platform on which to design effective Bfl-1 targeting therapeutics.
巻・号 12(2)
ページ 444-455
公開日 2017-2-17
DOI 10.1021/acschembio.6b00962
PMID 28026162
PMC PMC5320539
MeSH Amino Acid Sequence Antineoplastic Agents / chemistry* Antineoplastic Agents / pharmacology* Apoptosis Cell Line, Tumor Drug Resistance, Neoplasm* Humans Minor Histocompatibility Antigens / metabolism* Neoplasms / metabolism* Proto-Oncogene Proteins c-bcl-2 / metabolism*
IF 4.434
引用数 18
リソース情報
ヒト・動物細胞 StromaNKtert(RCB2350)