Shi Qi, Yin Shaoman, Kaluz Stefan, Ni Nanting, Devi Narra Sarojini, Mun Jiyoung, Wang Danzhu, Damera Krishna, Chen Weixuan, Burroughs Sarah, Mooring Suazette Reid, Goodman Mark M, Van Meir Erwin G, Wang Binghe, Snyder James P
Department of Chemistry, Emory University , Atlanta, Georgia 30322, United States.
Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Emory University School of Medicine , Atlanta, Georgia 30322, United States.
ACS Med Chem Lett. 2012 Jun 21;3(8):620-5. doi: 10.1021/ml300042k. eCollection 2012 Aug 9.
Hypoxia inducible factors (HIFs) are transcription factors that activate expression of multiple gene products and promote tumor adaptation to a hypoxic environment. To become transcriptionally active, HIFs associate with cofactors p300 or CBP. Previously, we found that arylsulfonamides can antagonize HIF transcription in a bioassay, block the p300/HIF-1α interaction, and exert potent anticancer activity in several animal models. In the present work, KCN1-bead affinity pull down, (14)C-labeled KCN1 binding, and KCN1-surface plasmon resonance measurements provide initial support for a mechanism in which KCN1 can bind to the CH1 domain of p300 and likely prevent the p300/HIF-1α assembly. Using a previously reported NMR structure of the p300/HIF-1α complex, we have identified potential binding sites in the p300-CH1 domain. A two-site binding model coupled with IC50 values has allowed establishment of a modest ROC-based enrichment and creation of a guide for future analogue synthesis.
缺氧诱导因子（HIFs）是激活多种基因产物表达并促进肿瘤适应缺氧环境的转录因子。为了具有转录活性，HIFs与辅因子p300或CBP结合。此前，我们发现芳基磺胺类药物在生物测定中可拮抗HIF转录，阻断p300/HIF-1α相互作用，并在多种动物模型中发挥强大的抗癌活性。在本研究中，KCN1磁珠亲和下拉、（14）C标记的KCN1结合以及KCN1表面等离子体共振测量为KCN1可结合p300的CH1结构域并可能阻止p300/HIF-1α组装的机制提供了初步支持。利用先前报道的p300/HIF-1α复合物的NMR结构，我们在p300-CH1结构域中确定了潜在的结合位点。结合IC50值的双位点结合模型实现了基于适度ROC的富集，并为未来类似物的合成创建了指导。
