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Insights into the Interaction Mechanism of DTP3 with MKK7 by Using STD-NMR and Computational Approaches

Authors :
Annamaria Sandomenico
Lorenzo Di Rienzo
Luisa Calvanese
Emanuela Iaccarino
Gabriella D’Auria
Lucia Falcigno
Angela Chambery
Rosita Russo
Guido Franzoso
Laura Tornatore
Marco D’Abramo
Menotti Ruvo
Edoardo Milanetti
Domenico Raimondo
Source :
Biomedicines, Vol 9, Iss 1, p 20 (2020)
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

GADD45β/MKK7 complex is a non-redundant, cancer cell-restricted survival module downstream of the NF-kB survival pathway, and it has a pathogenically critical role in multiple myeloma, an incurable malignancy of plasma cells. The first-in-class GADD45β/MKK7 inhibitor DTP3 effectively kills MM cells expressing its molecular target, both in vitro and in vivo, by inducing MKK7/JNK-dependent apoptosis with no apparent toxicity to normal cells. DTP3 combines favorable drug-like properties, with on-target-specific pharmacology, resulting in a safe and cancer-selective therapeutic effect; however, its mode of action is only partially understood. In this work, we have investigated the molecular determinants underlying the MKK7 interaction with DTP3 by combining computational, NMR, and spectroscopic methods. Data gathered by fluorescence quenching and computational approaches consistently indicate that the N-terminal region of MKK7 is the optimal binding site explored by DTP3. These findings further the understanding of the selective mode of action of GADD45β/MKK7 inhibitors and inform potential mechanisms of drug resistance. Notably, upon validation of the safety and efficacy of DTP3 in human trials, our results could also facilitate the development of novel DTP3-like therapeutics with improved bioavailability or the capacity to bypass drug resistance.

Details

Language :
English
ISSN :
22279059
Volume :
9
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Biomedicines
Publication Type :
Academic Journal
Accession number :
edsdoj.830a5a16f29844b08bd60fdf714a01ec
Document Type :
article
Full Text :
https://doi.org/10.3390/biomedicines9010020