"Design of Novel Pini Inhibitors Incorporating a p-Phospho-Glutamate An" by Jonathan Glen Meyer

Date of Award

2011

Degree Type

Thesis

Degree Name

Master of Science

Program

Biochemistry

Supervisor

Dr. Gilles Lajoie

Abstract

Pin1 is an enzyme essential to cell cycle regulation and has a key role in cancer proliferation. This thesis reports ongoing efforts to obtain a Pin1 inhibitor exhibiting an inhibition constant in the nanomolar range.

It was previously found that Pin 1 activity could be inhibited using a short proline containing peptide sequence which also contains a stereospecific (3- substituted a-amino acid. Several proline analogues were tested for greater inhibition against Pin1 than previously synthesized Cbz-/_-Glu((3-phos)-Pro-NH2. It was found that using full length Pin1 in the chymotrypsin-coupled photometric assay rendered different values than using only the catalytic PPIase domain for Cbz-Z_-Glu((3-phos)-Pro-NH2, Kj = 54.1+1.8 pM and 20 ± 0.9 pM respectively. The potential effectiveness of the synthesized inhibitors against Pin1 was assessed using the same convenient chymotrypsin-coupled photometric assay against full length Pin1.

This thesis describes the synthesis of two novel compounds which exhibited an increase in inhibition relative to Cbz-/_-Glu((3-phos)-Pro-NH2(Kj = 54.1+1.8 pM) with results in the micromolar range; Cbz-Z_-Glu(f3-phos)-Pip-NH2 (Kj = 45.4+1.1 pM) and Cbz-/_-Glu(p-phos)-Methylpiperazine (Kj = 22.7+1.4 pM)

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