Molecular mimicry-based repositioning of Nutlin-3 to anti-apoptotic Bcl-2 family proteins

Abstract

The identification of off-target binding of

drugs is a key to repositioning drugs to new therapeutic

categories. Here we show the universal interactions of the

p53 transactivation domain (p53TAD) with various antiapoptotic

Bcl-2 family proteins via a mouse double minute 2

(MDM2) binding motif, which play an important role in

transcription-independent apoptotic pathways of p53. Interestingly,

our structural studies reveal that the anti-apoptotic

Bcl-2 family proteins and MDM2 share a similar

mode of interaction with the p53TAD. On the basis of this

close molecular mimicry, our NMR results demonstrate that

the potent MDM2 antagonists Nutlin-3 and PMI bind to the

anti-apoptotic Bcl-2 family proteins in a manner analogous

to that with the p53TAD.