Discovery, Development, and Cellular Delivery of Potent and Selective Bicyclic Peptide Inhibitors of Grb7 Cancer Target

Journal of Medicinal Chemistry
Gabrielle M WatsonJacqueline A Wilce

Abstract

Grb7 is a signaling protein with critical roles in tumor cell proliferation and migration and an established cancer therapeutic target. Here we explore chemical space to develop a new bicyclic peptide inhibitor, incorporating thioether and lactam linkers that binds with affinity (KD = 1.1 μM) and specificity to the Grb7-SH2 domain. Structural analysis of the Grb7-SH2/peptide complex revealed an unexpected binding orientation underlying the binding selectivity by this new scaffold. We further incorporated carboxymethylphenylalanine and carboxyphenylalanine phosphotyrosine mimetics and arrived at an optimized inhibitor that potently binds Grb7-SH2 (KD = 0.13 μM) under physiological conditions. X-ray crystal structures of these Grb7-SH2/peptide complexes reveal the structural basis for the most potent and specific inhibitors of Grb7 developed to date. Finally, we demonstrate that cell permeable versions of these peptides successfully block Grb7 mediated interactions in a breast cancer cell line, establishing the potential of these peptides in the development of novel therapeutics targeted to Grb7.

References

Nov 1, 1995·Protein Science : a Publication of the Protein Society·C N PaceT Gray
Aug 14, 1999·The Journal of Biological Chemistry·D C Han, J L Guan
Jan 26, 2002·The Journal of Biological Chemistry·Stephanie C PeroDavid N Krag
Oct 31, 2003·Expert Reviews in Molecular Medicine·Stephanie C PeroDavid N Krag
May 28, 2004·Journal of Medicinal Chemistry·Nguyen-Hai NamKeykavous Parang
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jun 7, 2005·Biochimica Et Biophysica Acta·James R MaioloElizabeth A Ottinger
Apr 6, 2006·Journal of the National Cancer Institute·Shinji TanakaShigeki Arii
Dec 14, 2006·Acta Crystallographica. Section D, Biological Crystallography·Airlie J McCoy
Jul 14, 2007·The Biochemical Journal·Samir El-AndaloussiUlo Langel
Sep 23, 2009·Acta Crystallographica. Section D, Biological Crystallography·Nigel W MoriartyPaul D Adams
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Apr 15, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Yajun WangHextan Y S Ngan
Jul 17, 2010·Breast Cancer Research and Treatment·Betsy RamseyShiuh-Wen Luoh
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·T Geoff G BattyeAndrew G W Leslie
Oct 19, 2011·Breast Cancer Research and Treatment·Orsi GiriczParaic A Kenny
Jan 4, 2012·Journal of Molecular Recognition : JMR·Menachem J GunzburgJacqueline A Wilce
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Pavel V AfoninePaul D Adams
Jun 13, 2012·Chembiochem : a European Journal of Chemical Biology·Justin S QuartararoJoshua A Kritzer
Feb 12, 2013·Chemical Society Reviews·Dziyana KraskouskayaPatrick T Gunning
Mar 19, 2013·Biopolymers·Menachem J GunzburgJacqueline A Wilce
Jun 4, 2013·Trends in Pharmacological Sciences·Andrei A IvanovHaian Fu
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans, Garib N Murshudov
Jan 28, 2014·Breast Cancer Research and Treatment·Reece C C LimJacqueline A Wilce
Sep 10, 2014·Chemical Society Reviews·Yu Heng LauDavid R Spring
Feb 11, 2015·Biopolymers·Meng GaoHang Yin
Sep 12, 2015·Journal of Medicinal Chemistry·Gabrielle M WatsonJacqueline A Wilce
Apr 7, 2016·Nature Reviews. Drug Discovery·Duncan E ScottJohn Skidmore
Jun 4, 2016·Scientific Reports·Menachem J GunzburgJacqueline A Wilce

❮ Previous
Next ❯

Citations

Feb 23, 2020·International Journal of Molecular Sciences·Gabrielle M Watson, Jacqueline A Wilce
Jun 5, 2019·Journal of Cellular Physiology·Xiaqing YuZhongwei Lv
Oct 20, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Jianrong SangJacqueline A Wilce
Nov 30, 2019·Organic & Biomolecular Chemistry·Robert A Cerulli, Joshua A Kritzer
Apr 18, 2019·Beilstein Journal of Organic Chemistry·Iteng Ng-ChoiMarta Planas
Feb 6, 2020·Trends in Biochemical Sciences·Zachary R CrookJames M Olson

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.