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SUMMARY;LANGUAGE=en-us:Danette Daniels: Characterizing degradation kinetics 
 and cellular mechanisms of PROTAC compounds
DESCRIPTION:Company Representative\nSpeaker: Danette Daniels\nInstitution: 
 Promega\, USA\nHost: Joe Lewis\nAbstract: A new generation of pharmacologi
 c compounds resulting in degradation of target proteins\, termed degronomi
 ds or PROTACs\, hold significant therapeutic potential with possible prolo
 nged pharmacodymanics\, improved potency\, and ability to target proteins 
 previously thought of as  undruggable . These degradation compounds are bi
 valent inhibitors consisting of two components\; an inhibitor which specif
 ically binds to the target protein bridged via a linker to an inhibitor th
 at recruits ubiquitin machinery. The machinery proteins predominantly util
 ized are von Hippel-Lindau tumor suppressor (VHL) and Cereblon (CRBN)\, bo
 th of which are adaptor proteins of much larger and distinctive ubiquitin 
 E3 ligase complexes.  In this study we compare the mechanisms of degradati
 on of bromodomain BET family members mediated through bivalent inhibitors 
 consisting of JQ1 tethered to either VHL or CRBN recruiters\, termed MZ1 a
 nd dBET1 respectively. We explore dose-dependent kinetics of degradation\, 
 persistence of degradation\, target recovery\, ubiquitination of target\, 
 and live cell monitoring of the induced interaction with the respective E3 
 ligase components.  To facilitate the above studies we have endogenously t
 agged BET family members with an 11 amino peptide\, termed HiBiT\, using t
 he CRISPR/Cas9 system.  The HiBiT peptide\, which has high affinity for an
 d can complement with the LgBiT protein to produce NanoBiT luminescence\, 
 allows for highly sensitive detection of endogenous protein levels in livi
 ng cells\, and also can serve as a BRET energy donor to study protein inte
 ractions. Our data show varying degradation rates\, persistence\, and reco
 very of BET family members between MZ1 and dBET1 treatments\, as well as d
 ifferences amongst BET family members using the same degradation compound.  
 These studies further the understanding of mechanism facilitated by degrad
 ation compounds\, highlight the differential responses of BET family membe
 rs\, and also how the choice of E3 ligase component is an important consid
 eration in the therapeutic development of this new class of compounds.\n
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