Philochem AG, Wolfgang-Pauli-Str 10, 8093 Zürich, Switzerland.
ChemMedChem. 2010 Apr 6;5(4):584-90. doi: 10.1002/cmdc.200900520.
Bcl-xL is an antiapoptotic member of the Bcl-2 protein family and an attractive target for the development of anticancer agents. Here we describe the isolation of binders to Bcl-xL from a DNA-encoded chemical library using affinity-capture selections and massively parallel high-throughput sequencing of >30,000 sequence tags of library members. The most potent binder identified, compound 19/93 [(R)-3-(amido indomethacin)-4-(naphthalen-1-yl)butanoic acid], bound to Bcl-xL with a dissociation constant (K(d)) of 930 nM and was able to compete with a Bak-derived BH3 peptide, an antagonist of Bcl-xL function.
Bcl-xL 是 Bcl-2 蛋白家族的一种抗凋亡成员，也是开发抗癌药物的有吸引力的靶点。在这里，我们描述了使用亲和捕获筛选和对 >30,000 个文库成员的序列标签进行大规模平行高通量测序，从 DNA 编码的化学文库中分离出 Bcl-xL 结合物。鉴定出的最有效的结合物 19/93[（R）-3-（氨甲酰基吲哚美辛）-4-（萘-1-基）丁基]酸]，与 Bcl-xL 的解离常数（K(d)）为 930 nM，并能够与 Bak 衍生的 BH3 肽竞争，Bak 衍生的 BH3 肽是 Bcl-xL 功能的拮抗剂。
