DISCOVERY OF PEPTIDE ANTICANCER DRUGS

  • Lam, Kit (PI)
  • Lebl, Michael (PI)
  • Hruby, Victor (PI)
  • Schlessinger, Joseph (PI)
  • Ullrich, Axel (PI)
  • Hersh, Evan (PI)
  • Salmon, Sydney (PI)

Project: Research project

Description

Our long-range objective of this proposed NCDDG Cooperative Agreement is to
identify and develop synthetic peptides which have major antitumor activity
against common and often refractory forms of cancer including cancers of
the breast, prostate, lung, colon, and melanoma, and drug-resistant
leukemias and lymphomas. The scientific basis for this proposal is a new
"breakthrough" technology for rapidly producing and screening large
libraries comprised of millions of synthetic peptides produced via a novel
random synthesis technique which produces single peptide entities on
individual solid phase beads. This capability to produce such libraries
has been coupled to rapid techniques to screen the libraries with two
complementary strategies. The first technique involves direct molecular
probing against cancer-associated receptors such as the Epidermal Growth
Factor Receptor, and p185 HER2/neu. The second technique employs libraries
specially designed to permit peptides to be tested in solution against
relevant human cancer cell lines. The synthetic procedures used to produce
the libraries are very versatile and permit incorporation of D as well as
L amino acids, or other designer amino acids, and permit the creation of
libraries with defined conformational constraints including cyclic
peptides. Once peptides are identified which bind to the natural ligand
acceptor site in cancer-associated receptors, or which selectively inhibit
the in vitro growth of tumor cells, the relevant peptides on the "active
beads" will be sequenced and resynthesized for binding affinity,
biochemical and biologic studies. Using molecular modeling and peptide
conformational and topographical constraining techniques, drug leads will
be converted into candidate peptide drugs with favorable pharmacokinetic
properties. The candidate drugs are then tested in both in vitro and in
vivo tumor systems with the relevant human tumor (e.g. in SCID mice).
Active compounds will also be provided to the NCI on a discrete basis for
testing through its screening program. The feasibility of our approach has
already been established in initial experiments wherein libraries
containing at least 2.5 million peptides have been synthesized and from
which individual peptides from active beads have been isolated with cancer-
receptor binding activity, or inhibition of cancer cell growth. We
therefore believe that the potential for discovery of major new anti-tumor
agents with this approach by the scientific team assembled is extremely
promising.
StatusFinished
Effective start/end date8/21/9210/31/96

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

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Early Detection of Cancer
Proto-Oncogene Proteins c-kit
Peptide Library
Epidermal Growth Factor Receptor
Peptides
Libraries
ErbB-2 Receptor
Fibroblast Growth Factor Receptors
Peptide Receptors
Neoplasms
Color
Staining and Labeling
Ligands
Technology
Enzymes
Growth
Pharmaceutical Preparations
Proteins

ASJC

  • Medicine(all)