Discovery and characterization of novel peptide inhibitors of the NRF2/MAFG/DNA ternary complex for the treatment of cancer.

Autor: Simov V; Merck & Co., Inc., Chemistry, 33 Avenue Louis Pasteur, Boston, MA 02127, USA. Electronic address: vladimir_simov@merck.com., Altman MD; Merck & Co., Inc., Chemistry, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Bianchi E; Peptides and Small Molecules R&D, IRBM, Via Pontina, 30,600, 00071 Pomezia RM, Italy., DelRizzo S; Peptides and Small Molecules R&D, IRBM, Via Pontina, 30,600, 00071 Pomezia RM, Italy., DiNunzio EN; Merck & Co., Inc., Chemistry, 2000 Galloping Hill Road, K-15, Kenilworth, NJ 07033, USA., Feng G; Merck & Co., Inc., Quantitative Biosciences, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Goldenblatt P; Merck & Co., Inc., Quantitative Biosciences, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Ingenito R; Peptides and Small Molecules R&D, IRBM, Via Pontina, 30,600, 00071 Pomezia RM, Italy., Johnson SA; Merck & Co., Inc., Chemistry, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Mansueto MS; Merck & Co., Inc., Quantitative Biosciences, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Mayhood T; Merck & Co., Inc., Chemistry, 2000 Galloping Hill Road, K-15, Kenilworth, NJ 07033, USA., Mortison JD; Merck & Co., Inc., Chemistry, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Serebrov V; Merck & Co., Inc., Quantitative Biosciences, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Sondey C; Merck & Co., Inc., Quantitative Biosciences, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Sriraman V; Merck & Co., Inc., Quantitative Biosciences, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Tucker TJ; Merck & Co., Inc., Chemistry, 770 Sumneytown Pike, West Point, PA 19486, USA., Walji A; Merck & Co., Inc., Chemistry, 770 Sumneytown Pike, West Point, PA 19486, USA., Wan H; Merck & Co., Inc., PPDM, 126 East Lincoln Avenue, Rahway, NJ 07065, USA., Yue Y; Merck & Co., Inc., Biology, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., Stoeck A; Merck & Co., Inc., Biology, 33 Avenue Louis Pasteur, Boston, MA 02127, USA., DiMauro EF; Merck & Co., Inc., Chemistry, 33 Avenue Louis Pasteur, Boston, MA 02127, USA.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Nov 15; Vol. 224, pp. 113686. Date of Electronic Publication: 2021 Jul 07.
DOI: 10.1016/j.ejmech.2021.113686
Abstrakt: Pathway activating mutations of the transcription factor NRF2 and its negative regulator KEAP1 are strongly correlative with poor clinical outcome with pemetrexed/carbo(cis)platin/pembrolizumab (PCP) chemo-immunotherapy in lung cancer. Despite the strong genetic support and therapeutic potential for a NRF2 transcriptional inhibitor, currently there are no known direct inhibitors of the NRF2 protein or its complexes with MAF and/or DNA. Herein we describe the design of a novel and high-confidence homology model to guide a medicinal chemistry effort that resulted in the discovery of a series of peptides that demonstrate high affinity, selective binding to the Antioxidant Response Element (ARE) DNA and thereby displace NRF2-MAFG from its promoter, which is an inhibitory mechanism that to our knowledge has not been previously described. In addition to their activity in electrophoretic mobility shift (EMSA) and TR-FRET-based assays, we show significant dose-dependent ternary complex disruption of NRF2-MAFG binding to DNA by SPR, as well as cellular target engagement by thermal destabilization of HiBiT-tagged NRF2 in the NCI-H1944 NSCLC cell line upon digitonin permeabilization, and SAR studies leading to improved cellular stability. We report the characterization and unique profile of lead peptide 18, which we believe to be a useful in vitro tool to probe NRF2 biology in cancer cell lines and models, while also serving as an excellent starting point for additional in vivo optimization toward inhibition of NRF2-driven transcription to address a significant unmet medical need in non-small cell lung cancer (NSCLC).
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: