Current Medicinal Chemistry - Volume 17, Issue 13, 2010

Resistance to the Bcr-Abl inhibitors approved for the treatment of chronic myeloid leukaemia (CML) may arise from different mechanisms, including Bcr-Abl amino acid mutations, gene amplification and mechanisms independent of Bcr-Abl. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, including the synthesis of new Bcr-Abl ATPcompetitive or non-ATP-competitive inhibitors, dual Aurora/Bcr-Abl inhibitors and multi-targeted kinase inhibitors. An alternative approach is the use of other compounds that do not bind directly to the Bcr-Abl protein; instead, these molecules act on several downstream pathways, regulated by or linked in different ways to Bcr-Abl, that lead to the malignant transformation of the cells. For this reason, farnesyl transferase inhibitors, MAPK inhibitors, Rac guanosine triphosphatase inhibitors, PI3K inhibitors, JAK inhibitors, Hsp90 inhibitors, mTOR inhibitors, PP2A activators and apoptosis inducers have been tested, alone or in combination with ATP-competitive inhibitors, against CML cell lines. This review discusses compounds that act on Bcr-Abl or different cell pathways and reports on the molecules active against the T315I mutation, particularly the most recent findings in this field. New molecules that are claimed by recent patents to be active on this mutation are also reported. When possible, the review will focus on medicinal chemistry in terms of chemical structure, mechanism of action and structure-activity relationships.

Changes to the epigenetic information within a cell play a significant role in cancer development and progression. These epigenetic changes are important in establishing the aberrant gene expression patterns that are a feature of cancer cell biology. We are currently experiencing a rapid advance in our understanding of how epigenetic information is written and interpreted in the cell, and the enzymes involved in these processes have been recognised as prime targets for therapeutic intervention. Reagents that target these enzymes have the potential to inhibit or reverse epigenetic changes in cancer cells. Evidence suggests that the aberrant regulation of two gene silencing pathways; involving DNA methylation and histone methylation, play an important role in cancer development. Considerable effort is being exerted in the development of inhibitors of these pathways. However, complex functional interactions exist between the DNA and histone methylation pathways, and these interactions will need to be considered in the design of inhibitory molecules. This review details current research into agents developed as inhibitors of these epigenetic pathways, focusing on the types of epigenetic modifications being targeted, interactions between these modifications and the use of these inhibitory agents in cancer treatment.

The outstanding physio-pathological role played by integrin receptors in living subjects motivates the enormous interest shown by scientists worldwide for this topic. More than twenty years of research has spanned across the structural and functional elucidation of these proteins and over their antagonism-based biomedical applications. The proof-ofconcept stage, aimed at identifying potent inhibitors, covered a decade of studies, and paved the way for a more advanced era of research where these antagonist molecules were thrown into the deep end of applicative studies. This review intends to summarize the major efforts conducted thus far and focuses on the design, synthesis and biomedical applications of cyclic RGD-containing αvβ3 integrin antagonists, in both their small and macromolecular formats. In particular, Chapters 1 and 2 offer a comprehensive outlook on the rational basis for the design of integrin inhibitors, Chapter 3 chronicles the biological and medical applications of monofunctional RGD integrin ligands both in their monomeric and multimeric asset, and Chapter 4 illustrates the potential of RGD-based multifunctional systems in molecular medicine.

Novel molecular genetic approaches, at genome-scale in different species allowed characterizing genes that have undergone recent selection. The interest in this research field is not limited to the natural curiosity about our evolutionary past, but it is also to identify novel susceptibility genes for neuropsychiatic disorders by pointing specific human traits, such as behavioral and cognitive abilities. Hypotheses have been proposed to relate specific psychiatric disorders to the origin of modern humans, as evidenced by the theory of Crow about schizophrenia. In the present review, we will focus on genes that underwent positive selection in humans or displayed a human specific evolutionary pattern and which were reported as associated with psychiatric disorders. This will include the (1) DRD4 gene associated with attentiondeficit/ hyperactivity disorder, located in a locus that underwent a positive selection; the (2) GABRB2 gene, a gene associated with schizophrenia and recently reported as the target of a positive selection; (3) MARK1, a candidate gene for autism that was reported as displaying a signature of adaptative evolution in the human lineage, and (4) the ADH and ALDH2 genes which are associated with alcoholism, and for which evidence of positive selection was identified in the human lineage since the divergence between humans and chimpanzees. Identification of novel candidate genes based on recent evolution selection, coupled to genome-wide strategies designed to detect rare structural variants, could lead to a better knowledge of the molecular mechanisms of neurodevelopmental disorders and might therefore help to develop new medical chemistry.

Type IV collagens are basement membrane (BM) proteins expressed in all tissues including the vasculature. COL4A1 and COL4A2, the most abundant type IV collagens, form heterotrimers with a 2:1 stoichiometry and each heterotrimer forms a triple helix along the length of the collagenous domains. Recently, mutations in COL4A1 on chromosome 13q34, encoding the α1 chain of type IV collagen, have been linked to a spectrum of cerebral small-vessel disease in humans, including perinatal intracerebral hemorrhage (ICH) with consequent porencephaly, adult-onset ICH, microbleeds, lacunar strokes, and leukoaraiosis, which follows an autosomal dominant pattern of inheritance. This variable phenotype has been named the “COL4A1 stroke syndrome”. In COL4A1 stroke syndrome most mutations are missense mutations involving a glycine residue, including G562E, G749S, G805R, G1130D, G1236R, G1423R, G720D, G1580R, and G755R. Mutations replacing a highly conserved hydrophobic glycine residue likely lead to synthesis of an abnormal protein with abnormal structure and inhibit heterotrimer secretion into the vascular BM, modify its structural properties (when imaged with electron microscopy BM is uneven, with inconsistent density and focal disruptions), and, thus, increase the fragility of the vessel wall when exposed to environmental factors. Although pathological changes in BM also occur in other tissues (mostly retina and kidney), the major site of vessel damage is the brain. In the present review article we will focus on the molecular basis of the COL4A1 stroke syndrome, summarize data on its variable phenotype, and explore additional questions concerning the possible genotype-phenotype correlations and the mechanisms leading to cerebral small-vessel disease in this clinically heterogeneous condition.

Natural as well as synthetic coumarins have recently drawn much attention due to its broad pharmacological activities. Many coumarins and their derivatives exert anti-coagulant, anti-tumor, anti-viral, anti-inflammatory and antioxidant effects, as well as anti-microbial and enzyme inhibition properties. The recognition of key structural features within coumarin family is crucial for the design and development of new analogues with improved activity and for the characterization of their mechanism of action and potential side effects. The different substituents in the coumarin nucleus strongly influence the biological activity of the resulting derivatives. Although some coumarins have been already characterized to evoke a particular biological activity, the challenge would be the design and synthesis of new derivatives with high specific activity for other pharmacological targets and define their mechanism of action to achieve new therapeutic drugs. The present review highligts the current progress in the development of coumarin scaffolds for drug discovery as novel anti-cancer agents. The major challenges about coumarins include the translation of current knowledge into new potential lead compounds and the repositioning of known compounds for the treatment of cancer.