HIGHLIGHTS
Biomedical
KEVIN BURGESS Texas A&M University, US
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max abs 1026 nm, max emis 1045 nm Flav7
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Flavylium fluors Cy-7 derivatives, cyanine dyes with seven connecting atoms between the heterocyclic end-groups, are widely used near-IR absorbing fluors. They are particularly valuable in applications that require sensitivity to long wavelengths. However, current designs for Cy-7 derivatives do not have absorption maxima beyond approximately 800nm, and that is why a recent report by Sletten et al is particularly exciting (Angew. Chem. Int. Ed., 2017, 56, 13126). They used a classical cyanine
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synthesis except with pyrillium salts having acidic methyl substituents to form the end groups. Several compounds in this series were prepared, but Flav7 stands out because it is quite emissive (quantum yield >0.1) and absorbs/emits over 1000nm (Figure 1).
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Selective CDK4/6 fluors in liver cancer Selective inhibitors of CDK4/6 are having a transformative effect on cancer treatment. Whereas the first generation of compounds in this area were non-selective for the CDK kinases, and therefore induce off- target effects, the latest inhibitors of only CDK4/6 in the series are much more useful. Compounds in this class are FDA
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H 1
Figure 3 Compound predicted to impede the p53•MDM2 interaction
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approved for treatment of some forms of cancer, and are in clinical trials for others. However, there is a mystery surrounding a widely used, selective CDK4/6 inhibitor,
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1 44 02 | 2018 F O O N 1-Ada N HN N
Figure 2 Palbociclb N
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Figure 1 Flav7 - a new cyanine derivative with exceptionally long absorption and emission wavelengths
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max abs 1026 nm, max emis 1045 nm Flav7
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max abs 1026 nm, max emis 1045 nm Flav7
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Matching PPIs to multicomponent reactions
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Domling and co-worker’s ANCHOR. QUERY routine takes a fragment that fits in a cavity at a protein-protein interface and evaluates a vast virtual library of compounds that can be prepared via multicomponent reactions for fit and docking score. This method facilitates hopping between scaffolds to evaluate inhibitors of protein- protein interactions (PPIs).
palbociclib F
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1 1-Ada 1-Ada
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1-Ada N N Some members of
the virtual library can be accessed via sequential multicomponent couplings, and this is one of the features that make that abstract set of compounds so vast.
Figure 4 Compound inhibiting PCSK9 synthesis
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max abs 1026 nm, max emis 1045 nm Flav7
palbociclib. The substrate of CDK4/6 kinases is retinoblastoma protein (Rb), but the compounds are active against some cancers that are Rb- negative. A network of groups in Taiwan established a mechanism by which palbociclib (Figure 2) inhibits proliferation of Rb-negative tumors (doi:10.1002/1878-0261.12072; Mol Oncol., 2017, 11, 1035). They discovered that the phosphatase PP5 is upregulated in hepatocellular cancer, and this causes downregulation of the 5’ AMP-activated protein kinase (AMPK) pathway. Treatment with palbociclib downregulates PP5 and re-activates the AMPK pathway that leads to apoptosis. Thus, by a fortunate twist in polypharmacology-fate, palbociclb, not some other selective CDK4/6 inhibitors, are active against Rb- negative liver cancer cells.
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Domling’s group used one set of sequential multicomponent couplings to access compounds like 1 (Figure 3) that ANCHOR.QUERY predicted would impede the p53•MDM2 interaction, one of the most important PPIs in oncology. In fact it does with 2µM Ki whereas the established inhibitor nutlin has a Ki or 0.04µM in the same assay (MedChemComm., 2017, 8, 1046). This is a very encouraging result
since nutlin was developed after extensive optimisation.
Small molecules that inhibit PCSK9 synthesis
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Another important PPI is that between the proteins PCSK9 and LDLR; disruption of PCSK9•LDLR by humanised mAbs is a validated target for reduction of LDL-cholesterol levels. The challenge in this field is to identify orally available small molecules that can replicate this behaviour. Pfizer has described the evolution of a set of compounds that do this indirectly, ie via suppressing the synthesis of PCSK9. That study involves synthesis, extensive pharmacokinetics, development of prodrugs, and mouse/monkey in vivo studies, all crammed into a communication that eventually reveals structures like compound 2 (Figure 4) (Angew. Chem. Int. Ed. Eng., 2017, 56, 16218).
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