Computational techniques are valuable tools for the discovery of protein-protein interaction inhibitors: the 14-3-3σ case

Bioorganic & Medicinal Chemistry Letters
Valentina CorradiMaurizio Botta

Abstract

Targeting the binding site of 14-3-3 proteins lets the release of partner proteins involved in cell cycle progression, apoptosis, cytoskeletal rearrangement and transcriptional regulation and may therefore be regarded as an alternative strategy to integrate conventional therapeutic approaches against cancer. In the present work, we report the identification of two new small molecule inhibitors of 14-3-3σ/c-Abl protein-protein interaction (BV01 and BV101) discovered by means of computational methods. The most interesting compound (BV01) showed a lethal dose (LD(50)) in the low micromolar range against Ba/F3 murine cell lines expressing the Imatinib (IM)-sensitive wild type Bcr-Abl construct and the IM-resistant Bcr-Abl mutation T315I. BV01 interaction with 14-3-3σ was demonstrated by NMR studies and elucidated by docking. It blocked the binding domain of 14-3-3σ, hence promoting the release of the partner protein c-Abl (the one not involved in Bcr rearrangement), and its translocation to both the nuclear compartment and mitochondrial membranes to induce a pro-apoptotic response. Our results advance BV01 as a confirmed hit compound capable of eliciting apoptotic death of Bcr-Abl-expressing cells by interfering with 14-3-3σ/c-Abl ...Continue Reading

References

Jun 4, 2013·Trends in Pharmacological Sciences·Andrei A IvanovHaian Fu
Jun 26, 2014·Future Medicinal Chemistry·Maria BartelChristian Ottmann
Mar 1, 2014·Future Medicinal Chemistry·Federico FalchiMaurizio Recanatini
Nov 10, 2015·Journal of Chemical Information and Modeling·Ylenia CauMarco Lalle
Jan 5, 2016·Journal of Chemical Information and Modeling·David K Johnson, John Karanicolas
Mar 14, 2014·Nature Reviews. Cancer·Tracy L NeroMichael W Parker
Feb 8, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Leire Iralde-LorenteMaurizio Botta
Jun 13, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Alice BalloneChristian Ottmann

Citations

Jan 23, 2004·Nature Reviews. Cancer·Heiko Hermeking
Apr 3, 2004·Nature Reviews. Drug Discovery·Michelle R Arkin, James A Wells
May 16, 2006·Seminars in Cancer Biology·Heiko Hermeking, Anne Benzinger
May 27, 2006·Seminars in Cancer Biology·Guri TzivionVitaly Balan
Feb 18, 2009·Traffic·Manuela ManciniMaria Alessandra Santucci

Related Concepts

Cell Cycle Progression
Transcriptional Regulation
Antineoplastic Agents
Apoptosis, Intrinsic Pathway
Protein C, human
Murine
Proto-Oncogene Proteins c-abl
YWHAQ gene
Protein C Measurement
Mitochondrial Membranes

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.