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

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.

DNA repair targeted therapy: The past or future of cancer treatment?

“…The inhibitor IBR2 disrupts the Rad51-BRC interaction, Rad51 multimerization, and enhances proteasome-mediated RAD51 protein degradation. The cellular effect of IBR2 included an increase in the sensitivity of MCF7 breast cancer cells to IR (Zhu et al, 2013). Further SAR analysis of IBR2 generated the stereo selective inhibitor IBR20 (Fig.…”

Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism

“…However, since all these compounds act through inhibiting MDM2 to restore p53 functions, they have limitation on cells with mutated or deleted p53. In the endeavor of seeking specific protein-protein interaction disruptors, we have taken a forward chemical genetics approaches and identified RAD51 inactivator 43 and Hec1/Nek2 disruptors 25 . Interestingly, disruption of RAD51-BRC interaction and RAD51 multimerization by IBR2 triggers RAD51 degradation in cancer cells through proteasome pathway.…”

Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

“…One methylene spacer shorter (5 vs 6) or longer (10 vs B02) reduced the potency of RAD51 functional inhibition. Restricting rotation (indane 11) or introducing potential charged isosteres, such as morpholine (7)(8) or pyridine to replace benzene (12)(13)(14), all reduced efficacy. Smaller alkanes (1-4) also displayed reduced activity.…”

“…RAD51 has been recognized as a potential oncotarget due to its critical role in HR, and contributes to an aggressive cellular phenotype and resistance to therapeutics. Several small molecule RAD51 inhibitors have been discovered by high-throughput screening of compound libraries, notably B02 [5][6][7] , the RI series [8][9][10] and the IBR2 series 11,12 ( Figure 1). Alternatively, a fragmentbased screening approach at Cambridge identified another series of compounds 13,14 ( Figure 1).…”