Use of large combinatorial chemical libraries for anticancer drug discovery

Sydney E. Salmon, Kit Lam, Stephen Felder, Helen Yeoman, Joseph Schlessinger, Axel Ullrich, Viktor Krchnak, Michal Lebl

Research output: Contribution to journalArticle

Abstract

A new technology for drug discovery (Selectide technology) has been developed which greatly extends the capability for rapid molecular and cellular screening to large libraries containing millions of chemically synthesized compounds. Using a split synthesis approach to condensation chemistry, we recognized that each individual compound of potential interest is located on a different solid phase resin bead. Screening for binding activity on the bead surface: In order to screen for biological activity, we used several cleavable linkers which could release a portion of the compound from each bead into the solution phase in each of two sequential steps. For libraries comprised of peptides, there is sufficient residual peptide on each bead to permit sequence determination via Edman degradation. For non-peptide libraries, a system of peptide encoding is used on each bead so that the structure of the non-peptide compound can be determined by decoding the information conveyed by the peptide (which can be sequenced). We have applied this technology to various areas of drug discovery including a major interest in the development of anticancer drugs. Molecular targets under evaluation include cell surface monoclonal immunoglobulin on B-cell lymphomas, the epidermal growth factor receptor, and the HER2-neu receptor. Solution phase screening with releasable libraries is being used to evaluate anti-tumor activity using a battery of human tumor cell lines. Based on data obtained thus far, we believe that the Selectide technology has the potential for discovering novel new anticancer drugs.

Original languageEnglish (US)
Pages (from-to)67-74
Number of pages8
JournalPharmaceutical Biology
Volume33
Issue numberS1
DOIs
StatePublished - 1995
Externally publishedYes

Fingerprint

Small Molecule Libraries
Drug Discovery
Libraries
Technology
Peptides
Peptide Library
B-Cell Antigen Receptors
B-Cell Lymphoma
Tumor Cell Line
Pharmaceutical Preparations
Sequence Analysis
Neoplasms

Keywords

  • Cancer
  • Combinatorial chemistry
  • Drug discovery
  • Peptides
  • Screening

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology
  • Pharmaceutical Science
  • Complementary and alternative medicine
  • Molecular Medicine

Cite this

Salmon, S. E., Lam, K., Felder, S., Yeoman, H., Schlessinger, J., Ullrich, A., ... Lebl, M. (1995). Use of large combinatorial chemical libraries for anticancer drug discovery. Pharmaceutical Biology, 33(S1), 67-74. https://doi.org/10.3109/13880209509067089

Use of large combinatorial chemical libraries for anticancer drug discovery. / Salmon, Sydney E.; Lam, Kit; Felder, Stephen; Yeoman, Helen; Schlessinger, Joseph; Ullrich, Axel; Krchnak, Viktor; Lebl, Michal.

In: Pharmaceutical Biology, Vol. 33, No. S1, 1995, p. 67-74.

Research output: Contribution to journalArticle

Salmon, SE, Lam, K, Felder, S, Yeoman, H, Schlessinger, J, Ullrich, A, Krchnak, V & Lebl, M 1995, 'Use of large combinatorial chemical libraries for anticancer drug discovery', Pharmaceutical Biology, vol. 33, no. S1, pp. 67-74. https://doi.org/10.3109/13880209509067089
Salmon, Sydney E. ; Lam, Kit ; Felder, Stephen ; Yeoman, Helen ; Schlessinger, Joseph ; Ullrich, Axel ; Krchnak, Viktor ; Lebl, Michal. / Use of large combinatorial chemical libraries for anticancer drug discovery. In: Pharmaceutical Biology. 1995 ; Vol. 33, No. S1. pp. 67-74.
@article{a473fec712d14104ab4816ad40c4b03d,
title = "Use of large combinatorial chemical libraries for anticancer drug discovery",
abstract = "A new technology for drug discovery (Selectide technology) has been developed which greatly extends the capability for rapid molecular and cellular screening to large libraries containing millions of chemically synthesized compounds. Using a split synthesis approach to condensation chemistry, we recognized that each individual compound of potential interest is located on a different solid phase resin bead. Screening for binding activity on the bead surface: In order to screen for biological activity, we used several cleavable linkers which could release a portion of the compound from each bead into the solution phase in each of two sequential steps. For libraries comprised of peptides, there is sufficient residual peptide on each bead to permit sequence determination via Edman degradation. For non-peptide libraries, a system of peptide encoding is used on each bead so that the structure of the non-peptide compound can be determined by decoding the information conveyed by the peptide (which can be sequenced). We have applied this technology to various areas of drug discovery including a major interest in the development of anticancer drugs. Molecular targets under evaluation include cell surface monoclonal immunoglobulin on B-cell lymphomas, the epidermal growth factor receptor, and the HER2-neu receptor. Solution phase screening with releasable libraries is being used to evaluate anti-tumor activity using a battery of human tumor cell lines. Based on data obtained thus far, we believe that the Selectide technology has the potential for discovering novel new anticancer drugs.",
keywords = "Cancer, Combinatorial chemistry, Drug discovery, Peptides, Screening",
author = "Salmon, {Sydney E.} and Kit Lam and Stephen Felder and Helen Yeoman and Joseph Schlessinger and Axel Ullrich and Viktor Krchnak and Michal Lebl",
year = "1995",
doi = "10.3109/13880209509067089",
language = "English (US)",
volume = "33",
pages = "67--74",
journal = "Pharmaceutical Biology",
issn = "1388-0209",
publisher = "Informa Healthcare",
number = "S1",

}

TY - JOUR

T1 - Use of large combinatorial chemical libraries for anticancer drug discovery

AU - Salmon, Sydney E.

AU - Lam, Kit

AU - Felder, Stephen

AU - Yeoman, Helen

AU - Schlessinger, Joseph

AU - Ullrich, Axel

AU - Krchnak, Viktor

AU - Lebl, Michal

PY - 1995

Y1 - 1995

N2 - A new technology for drug discovery (Selectide technology) has been developed which greatly extends the capability for rapid molecular and cellular screening to large libraries containing millions of chemically synthesized compounds. Using a split synthesis approach to condensation chemistry, we recognized that each individual compound of potential interest is located on a different solid phase resin bead. Screening for binding activity on the bead surface: In order to screen for biological activity, we used several cleavable linkers which could release a portion of the compound from each bead into the solution phase in each of two sequential steps. For libraries comprised of peptides, there is sufficient residual peptide on each bead to permit sequence determination via Edman degradation. For non-peptide libraries, a system of peptide encoding is used on each bead so that the structure of the non-peptide compound can be determined by decoding the information conveyed by the peptide (which can be sequenced). We have applied this technology to various areas of drug discovery including a major interest in the development of anticancer drugs. Molecular targets under evaluation include cell surface monoclonal immunoglobulin on B-cell lymphomas, the epidermal growth factor receptor, and the HER2-neu receptor. Solution phase screening with releasable libraries is being used to evaluate anti-tumor activity using a battery of human tumor cell lines. Based on data obtained thus far, we believe that the Selectide technology has the potential for discovering novel new anticancer drugs.

AB - A new technology for drug discovery (Selectide technology) has been developed which greatly extends the capability for rapid molecular and cellular screening to large libraries containing millions of chemically synthesized compounds. Using a split synthesis approach to condensation chemistry, we recognized that each individual compound of potential interest is located on a different solid phase resin bead. Screening for binding activity on the bead surface: In order to screen for biological activity, we used several cleavable linkers which could release a portion of the compound from each bead into the solution phase in each of two sequential steps. For libraries comprised of peptides, there is sufficient residual peptide on each bead to permit sequence determination via Edman degradation. For non-peptide libraries, a system of peptide encoding is used on each bead so that the structure of the non-peptide compound can be determined by decoding the information conveyed by the peptide (which can be sequenced). We have applied this technology to various areas of drug discovery including a major interest in the development of anticancer drugs. Molecular targets under evaluation include cell surface monoclonal immunoglobulin on B-cell lymphomas, the epidermal growth factor receptor, and the HER2-neu receptor. Solution phase screening with releasable libraries is being used to evaluate anti-tumor activity using a battery of human tumor cell lines. Based on data obtained thus far, we believe that the Selectide technology has the potential for discovering novel new anticancer drugs.

KW - Cancer

KW - Combinatorial chemistry

KW - Drug discovery

KW - Peptides

KW - Screening

UR - http://www.scopus.com/inward/record.url?scp=84907105923&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907105923&partnerID=8YFLogxK

U2 - 10.3109/13880209509067089

DO - 10.3109/13880209509067089

M3 - Article

AN - SCOPUS:84907105923

VL - 33

SP - 67

EP - 74

JO - Pharmaceutical Biology

JF - Pharmaceutical Biology

SN - 1388-0209

IS - S1

ER -