Design and Synthesis of Covalent Enzyme Inhibitors

Introduction. Fibroblast activation protein-? (FAP), an enzyme of the S9 protein family, was identified as a major player in the activation of the stroma required for tumor growth and proliferation and progression of cancer cells. In parallel, prolyl oligopeptidase (POP), an enzyme of the same family, has been found to be responsible for the production of a potent stimulator of angiogenesis and that its inhibition arrests the growth of cancer cells. Recently it was suggested that inhibiting both FAP, blocking stromal invasion, and POP, reducing angiogenesis may lead to growth arrest in different cancer cells types. This report turned our attention towards the design of dual inhibitors or drug combinations as potentially effective cancer therapies.
We have achieved inhibition of POP through the combined expertise of the Moitessier group in drug design and synthesis, of Dr. Juillerat-Jeannerets group (Lausanne, Switzerland) in biology and of the Mittermaier group in biophysics to better understand the binding mechanism of these covalent inhibitors and to develop higher throughput biological assays. Our lead molecules will now be further modified into dual POP/FAP inhibitors.

Objectives. In order to validate POP/FAP dual inhibitors or combination of selective inhibitors as cancer therapeutics and develop and test improved POP/FAP inhibitors, we propose to: use our computational drug design tools (Forecaster platform) to design novel dual inhibitors and to synthesize them in the laboratory. Biolgocial assays in other other labs will follow.
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Faculty Supervisor:

Nicolas Moitessier

Student:

Vivian Alvarez Islas

Partner:

Discipline:

Chemistry

Sector:

University:

McGill University

Program:

Globalink