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Barrier relief

No drug target inspires more confidence in the pharmaceutical and biotechnology industry than the kinase. Kinases are protein enzymes that use ATP to phosphorylate targets and, in doing so, often profoundly alter cellular signalling and then disease phenotypes. Because of the ease of purification of early kinases, their structures and in vitro assays were easily developed and miniaturized for high throughput robotic testing. Because of the simplicity of their enzymatic mechanism, substrates and products, assay readouts could be precisely engineered for multiple purposes. This led to an enormous knowledge base of kinase structure, function and behaviour and one of the largest existing knowledge bases of kinase inhibitor medicinal chemistry, synthetic schemes and structure-activity relationships at the biochemical, cellular animal and human levels.

There are probably more kinase inhibitor derived compounds dotting the chemical databases than any other class of chemicals, and nothing reassures your average medicinal chemist more than finding out that their work will be on a kinase inhibitor, rather than some naturally occurring compound or compound targeting some other enzyme or protein. Not surprisingly, the list of marketed kinase inhibitors is long and growing.

But that list suddenly looks very short when it comes to disease indications that involve the central nervous system and brain. Why? Meet a little thing called the “blood-brain barrier,” nature’s level 5 challenge for drugs in the body. Managed to overcome the herculean task of finding a manufactured, potent, specific drug-like inhibitor of your kinase that is metabolically stable and non-toxic in the body of animals/humans and can also penetrate cell membranes? Congratulations. None of that buys you any chance of crossing the blood-brain barrier to treat any condition involving the brain: Oh, like the biggest unmet medical need in history, Alzheimer’s disease. Not to mention schizophrenia, depression, seizures, stroke and a whole host of other urgent and prevalent unmet medical needs. The list of CNS kinase inhibitor program corpses is long and possibly in the trillions of dollars of wasted effort.

Fortunately, the drug discovery field has not given up. Recently, pharma experts Shi and Mader systematically studied the problem to map out the characteristics that distinguish CNS penetrant kinase inhibitors from those that fail to penetrate the CNS. Their roadmap looks compelling, providing clear ranges of predictive physicochemical properties, such as solubility proxies like cLogP, size and electrochemical features (hydrogen bond donors and polar surface area). More inspiring, it appears that the recently developed aggregate CNS-MPO score nicely takes all these properties into account correctly so that its single score can be used as a guiding metric for kinase inhibitor development.

And that’s only for physicochemical properties. Add in additional data from improved in vitro tests, such as the dual transcript MDR1-MDCK assay, and the force is strong with us! It all seems so easy now, but don’t forget, these advances are all about modeling the in vivo situation, and we at Genecentrix are into some next level stuff when it comes to that.

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