Cells repeatedly undergo biochemical changes to grow and divide, ie cell cycling. Many frequently used small molecule anti-cancer drugs (eg cis-platins, paclitaxel, vincristine, vinblastine, palbociclib) interfere with cell cycling. Kinase inhibitors (KIs) are small molecule drugs which occupy active sites of enzymes which transfer phosphate groups to proteins. Cyclin dependent kinases (CDKs) must bind another protein, a cyclin, to become active. Many KI drugs act via inhibition of CDKs. CDK9 acts as a cell cycling master switch. It is upregulated in most, possibly all, types of cancer. So far, two KIs for CDK9 are clinically used, but others are in trials. A general failing of CDK KIs is ...
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Cells repeatedly undergo biochemical changes to grow and divide, ie cell cycling. Many frequently used small molecule anti-cancer drugs (eg cis-platins, paclitaxel, vincristine, vinblastine, palbociclib) interfere with cell cycling. Kinase inhibitors (KIs) are small molecule drugs which occupy active sites of enzymes which transfer phosphate groups to proteins. Cyclin dependent kinases (CDKs) must bind another protein, a cyclin, to become active. Many KI drugs act via inhibition of CDKs. CDK9 acts as a cell cycling master switch. It is upregulated in most, possibly all, types of cancer. So far, two KIs for CDK9 are clinically used, but others are in trials. A general failing of CDK KIs is tumors become resistant, typically after ~3 months, then cancer progresses. Tumors can acquire resistance by changing (mutating) their active sites to exclude KIs. An approach which does not rely on kinase inhibition is required to overcome this. An emerging approach is to use small molecules called PROTACS. PROTACS destroy targeted proteins, whereas KIs make just them temporarily inactive. One PROTACS molecule can destroy many protein molecules, but KIs can only inactivate one. Some of the earliest PROTACS are progressing through clinical trials. They have the potential to delay or even overcome acquired immunity. However, PROTACS research is limited because their discovery involves slow and inefficient trial-and-error optimization. We have a PROTACS we designed that can destroy both CDK9 and its activator, cyclin T in breast cancer cells. Further, we have made the first PROTACS to glow under UV light (fluoresce); we call them FLUORTACs. FLUORTACS can be observed in particular cell regions. We have developed three which decompose CDK9 and cyclin T. Our hypothesis is FLUORTACS can be tested efficiently, and designed to target cell regions where CDK9 and cyclin T operate, hence degrade them more effectively. This would be impossible for normal PROTACS.
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