The probability of speciation on an interaction network with unequal substitution rates.

Speciation is characterized by the development of reproductive isolating barriers between diverging groups. A seminal paper of a mathematical model of speciation was published by Orr (1995), extended by Livingstone et al. (2012) to incorporate interaction networks.

Isoindolinone ureas: a novel class of KDR kinase inhibitors.

A series of substituted isoindolinone ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 14c, are potent inhibitors of KDR both enzymatically (< 50 nM) and cellularly < or = 100 nM). A 3D KDR/CDK2/MAP kinase overlay model with several structurally related tyrosine kinase inhibitors was used to predict the binding interactions of the isoindolinone ureas with the KDR active site.

Heterocyclic ketones as inhibitors of histone deacetylase.

Several heterocyclic ketones were investigated as potential inhibitors of histone deacetylase. Nanomolar inhibitors such as 22 and 25 were obtained, the anti-proliferative activity of which were shown to be mediated by HDAC inhibition.

Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.

A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1.