Christopher Lum

2,5-Diaminopyrimidines and 3,5-disubstituted azapurines as inhibitors of glycogen synthase kinase-3 (GSK-3).

The discovery of two classes of pyrimidine-based inhibitors of GSK-3 is described. Optimization of these series led to inhibitors with IC(50)<10nM and >100-fold selectivity over Aurora A kinase. A proposed binding mode of 21b is presented. One compound (33) of the pyrimidine series showed promising pharmacokinetic parameters.

Anti-HIV-1 entry optimization of novel imidazopiperidine-tropane CCR5 antagonists

A novel series of imidazopiperidine-tropane CCR5 antagonists is described. The series was optimized for anti-HIV-1 potency using a set of phenotypic viral entry assays. This strategy resulted in the identification of several very potent (IC(50)<10nM) inhibitors of HIV-1 entry. One compound (40) was further profiled and was found to have attractive selectivity, pharmacokinetic, and antiviral properties.

Optimization of α-ketoamide based p38 inhibitors through modifications to the region that binds to the allosteric site

We have optimized a novel series of potent p38 MAP kinase inhibitors based on an alpha-ketoamide scaffold through structure based design that due to their extended molecular architecture bind, in addition to the ATP site, to an allosteric pocket. In vitro ADME, in vivo PK and efficacy studies show these compounds to have drug-like characteristics and have resulted in the nomination of a development candidate which is currently in phase II clinical trials for the oral treatment of inflammatory conditions.

Synthesis of 3-alkoxyazetidin-2-ones: Dipeptide mimics

Abstract Several dipeptide mimics, 3-alkoxyazetidin-2-ones, were prepared in a diastereoselective fashion by the direct displacement of a scalemic triflate with 3-hydroxyazetidin-2-ones. The scope and limitation are presented.

(1-Benzimidazolonyl)alanine (Bia): preliminary investigations into a potential tryptophan mimetic ☆

Abstract The new amino acid (1-benzimidazolonyl)alanine (Bia) was synthesized as a potential biomimetic replacement of tryptophan. The replacement of tryptophan with this amino acid in a truncated analog of p53 showed nearly identical binding to HDM2 as the same length of the natural peptide. Similar peptides containing 1- and 2-naphthylalanine in lieu of Trp showed weaker binding than either of the other peptides. The synthesis of Bia and the binding of the p53 analogs to HDM2 are reported.