Binding Model for the Interaction of Anticancer Arylsulfonamides with the p300 Transcription Cofactor

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• 作者：Qi Shi ; Shaoman Yin ; Stefan Kaluz ; Nanting Ni ; Narra Sarojini Devi ; Jiyoung Mun ; Danzhu Wang ; Krishna Damera ; Weixuan Chen ; Sarah Burroughs ; Suazette Reid Mooring ; Mark M. Goodman ; Erwin G. Van Meir ; Binghe Wang ; James P. Snyder
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：3
• 期：8
• 页码：620-625
• 全文大小：312K
• 年卷期：v.3,no.8(August 9, 2012)
• ISSN：1948-5875

文摘

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-1伪 interaction, and exert potent anticancer activity in several animal models. In the present work, KCN1-bead affinity pull down, ¹⁴C-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-1伪 assembly. Using a previously reported NMR structure of the p300/HIF-1伪 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.

Keywords:

hypoxia; solid tumors; p300; HIF arylsulfonamide inhibitors; binding model; QSAR; KCN1