公开(公告)号：US20150246946A1

公开(公告)日：2015-09-03

申请号：US14432729

申请日：2013-10-01

Applicant: AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH

Inventor： Thomas Leonard Joseph ,  Chandra Shekhar Verma ,  David Phillip Lane ,  Christopher John Brown

IPC: C07K7/06 ,  A61K38/08

CPC classification number: C07K7/06 ,  A61K38/00 ,  A61K38/08 ,  A61K38/10 ,  A61K45/06 ,  C07K7/08 ,  A61K2300/00

Abstract: By using a phage display derived peptide as an initial template, compounds have been developed that are highly specific against Mdm2/Mdm4. These compounds exhibit greater potency in p53 activation and protein-protein interaction assays than a compound derived from the p53 wild-type sequence. Unlike nutlin, a small molecule inhibitor of Mdm2/Mdm4, the phage derived compounds can arrest cells resistant to p53 induced apoptosis over a wide concentration range without cellular toxicity, suggesting they are highly suitable for cyclotherapy.

Abstract translation: 通过使用噬菌体展示衍生肽作为初始模板，开发了对Mdm2 / Mdm4具有高度特异性的化合物。 与来自p53野生型序列的化合物相比，这些化合物在p53活化和蛋白质 - 蛋白质相互作用测定中表现出更大的效力。 与Mdm2 / Mdm4的小分子抑制剂nutlin不同，噬菌体衍生的化合物可以在宽的浓度范围内阻止对p53诱导的细胞凋亡的细胞，而无细胞毒性，表明它们非常适合于环境疗法。

公开(公告)号：US20150276755A1

公开(公告)日：2015-10-01

申请号：US14438469

申请日：2013-10-25

Applicant: AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH

Inventor： Farid Ghadessy ,  Chandra Shekhar Verma ,  David Philip Lane ,  Jia Wei Siau ,  Thomas Leonard Joseph ,  Adelene Yen Ling Sim

IPC: G01N33/68 ,  C12Q1/68

CPC classification number: G01N33/6845 ,  C12Q1/6883 ,  C12Q2600/156 ,  G01N2333/4748 ,  G01N2333/9015 ,  G01N2500/02

Abstract: The present disclosure provides a method of determining resistance of a biological molecule to inhibition of its interaction with a target molecule by an inhibitor of the biological molecule, the method comprising the steps of: a) co-compartmentalizing a gene encoding the biological molecule with the target molecule, or a gene encoding the biological molecule with a gene encoding the target molecule into an aqueous droplet disposed within a water-in-oil emulsion, and b) assaying for a complex comprising the biological molecule and the target molecule upon expression of the gene encoding the biological molecule and the gene encoding the target molecule, wherein detection of the complex in the presence of the inhibitor indicates that the biological molecule is resistant to inhibition of its interaction with the target molecule by the inhibitor. Also provided are mutated HDM2 ubiquitin ligase polypeptides exhibiting resistance to Nutlin inhibition of p53 binding.

Abstract translation: 本公开提供了一种确定生物分子对生物分子的抑制剂与靶分子的相互作用的抗性的方法，所述方法包括以下步骤：a）将编码生物分子的基因与 目标分子或编码具有编码靶分子的基因的生物分子的基因转化成布置在油包水乳液中的水滴，以及b）在表达后，测定包含生物分子和靶分子的复合物 编码生物分子的基因和编码靶分子的基因，其中在抑制剂存在下检测复合物表明生物分子对抑制剂与靶分子的相互作用的抑制具有抗性。 还提供了显示出对Nutlin抑制p53结合的抗性的突变的HDM2泛素连接酶多肽。