A novel small molecule RAD51 inactivator overcomes imatinib‐resistance in chronic myeloid leukaemia

EMBO Molecular Medicine

Jiewen Zhu³  Longen Zhou³  Guikai Wu³  Heiko Konig¹  Xiaoqin Lin³  Guideng Li³  Xiao-Long Qiu³  Chi-Fen Chen³  Chun-Mei Hu³  Erin Goldblatt³  Ravi Bhatia¹  A. Richard Chamberlin²  Phang-Lang Chen⁴ 

[1] Division of Hematology and Bone Marrow Transplantation, City of Hope National Medical Center, Duarte, CA, USA;Department of Chemistry, University of California, Irvine, CA, USA;Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA, USA;E-mail address: 关键词: cancer;    CML;    inhibitor;    RAD51;    small molecule;   

DOI  :  10.1002/emmm.201201760

来源: Wiley

【 摘 要 】

Abstract

RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome-mediated RAD51 protein degradation, reduces ionizing radiation-induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib-resistant CML model bearing the T315I Bcr-abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34⁺ progenitor cells from CML patients resistant to known BCR-ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad-spectrum therapeutics for difficult-to-treat cancers.

【 授权许可】

Unknown   
Copyright © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.