Design, synthesis, and docking studies of peptidomimetics based on HER2-herceptin binding site with potential antiproliferative activity against breast cancer cell lines.
Epidermal growth factor receptor kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 occurs frequently in breast, ovarian, and lung cancers, making it an important therapeutic target in the treatment of cancer. Blocking HER2-mediated signaling with antibodies or small molecules has been shown to be effective in inhibiting cell growth. After analyzing the crystal structure of the HER2-herceptin complex, several peptidomimetics (HERP5, 6, and 7) were designed to inhibit HER2-mediated signaling for cell growth. We have used an in silico screening method to investigate the chemical diversity of the designed compounds. autodock software was used to dock the different analogs of HERP5 and HERP7 with HER2 protein extracellular domain. A total of 53 compounds were docked to HER2 protein, and their binding modes were analyzed in terms of docking energy, hydrogen bonding, and hydrophobic interactions. Compounds that exhibited low-energy docked structures were chosen for chemical synthesis and biological activity. Two of the compounds (HERP5 and HERP7) exhibited antiproliferative activity, with IC(50) values of 0.396 microm and 0.143 microm, respectively, against SKBR-3 cell lines (breast cancer cell lines) that overexpress HER2 protein.
Satyanarayanajois
Seetharama
S
Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71201, USA. jois@ulm.edu
Villalba
Stephanie
S
Jianchao
Liu
L
Lin
Go Mei
GM
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D001665:Binding Sites; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D005260:Female; D006801:Humans; D007529:Isoflavones; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007529:Isoflavones; D010455:Peptides; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C576978:7-(O)-carboxymethyl daidzein N-t-Boc-hexylenediamine conjugate
Cancer Lett. 2008 Oct 8;269(2):243-61
18550275
Endocr Relat Cancer. 2002 Dec;9(4):249-66
12542402
J Biol Chem. 2005 Jan 7;280(1):54-63
15507452
Bioorg Med Chem Lett. 2005 Nov 1;15(21):4774-9
16111887
Cancer Res. 2001 Jun 15;61(12):4744-9
11406546
J Biol Chem. 2002 Aug 2;277(31):28330-9
12011054
J Med Chem. 2003 Jan 2;46(1):49-63
12502359
Br J Surg. 2002 Mar;89(3):262-71
11872048
Cancer Res. 2001 Dec 15;61(24):8887-95
11751413
Pharmacol Ther. 1999 May-Jun;82(2-3):241-50
10454201
N Engl J Med. 2001 Mar 15;344(11):783-92
11248153
J Clin Oncol. 1999 Sep;17(9):2639-48
10561337
Nat Rev Cancer. 2005 May;5(5):341-54
15864276
Semin Oncol. 2004 Oct;31(5 Suppl 10):6-13
15490369
J Immunol. 2007 Jul 1;179(1):472-82
17579068
Clin Cancer Res. 2003 Nov 1;9(14):5078-84
14613984
J Med Chem. 1997 Jun 20;40(13):2085-101
9207949
Oncol Rep. 2005 Jan;13(1):133-7
15583814
Nature. 2003 Feb 13;421(6924):756-60
12610629
Oncogene. 2000 Dec 27;19(56):6550-65
11426640
J Comput Chem. 2007 Apr 30;28(6):1145-52
17274016
Oncogene. 2003 Sep 29;22(42):6570-8
14528282
Mol Cell. 2003 Sep;12(3):541-52
14527402
J Immunol Methods. 1983 Dec 16;65(1-2):55-63
6606682
Oncologist. 2004;9(1):58-67
14755015
J Med Chem. 2003 Oct 23;46(22):4657-68
14561085
Cancer Cell. 2004 Apr;5(4):317-28
15093539
Cancer Res. 1988 Feb 1;48(3):589-601
3335022
Cancer Cell. 2002 Aug;2(2):127-37
12204533
Cancer Res. 2004 Jun 1;64(11):3958-65
15173008
Oncogene. 2004 Jan 29;23(4):883-93
14661053