Structure-guided design of pyridoclax derivatives based on Noxa / Mcl-1 interaction mode.

Abstract:

:Protein-protein interactions are attractive targets because they control numerous cellular processes. In oncology, apoptosis regulating Bcl-2 family proteins are of particular interest. Apoptotic cell death is controlled via PPIs between the anti-apoptotic proteins hydrophobic groove and the pro-apoptotic proteins BH3 domain. In ovarian carcinoma, it has been previously demonstrated that Bcl-xL and Mcl-1 cooperate to protect tumor cells against apoptosis. Moreover, Mcl-1 is a key regulator of cancer cell survival and is a known resistance factor to Bcl-2/Bcl-xL pharmacological inhibitors making it an attractive therapeutic target. Here, using a structure-guided design from the oligopyridine lead Pyridoclax based on Noxa/Mcl-1 interaction we identified a new derivative, active at lower concentration as compared to Pyridoclax. This new derivative selectively binds to the Mcl-1 hydrophobic groove and releases Bak and Bim from Mcl-1 to induce cell death and sensitize cancer cells to Bcl-2/Bcl-xL targeting strategies.

journal_name

Eur J Med Chem

authors

Hedir S,De Giorgi M,Fogha J,De Pascale M,Weiswald LB,Brotin E,Marekha B,Denoyelle C,Denis C,Suzanne P,Gautier F,Juin P,Ligat L,Lopez F,Carlier L,Legay R,Bureau R,Rault S,Poulain L,Oliveira Santos JS,Voisin-Chiret

doi

10.1016/j.ejmech.2018.10.003

subject

Has Abstract

pub_date

2018-11-05 00:00:00

pages

357-380

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30865-1

journal_volume

159

pub_type

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