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Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation
journal contribution
posted on 2018-11-16, 00:00 authored by Philipp
M. Cromm, Kusal T. G. Samarasinghe, John Hines, Craig M. CrewsEnzymatic inhibition has proven to
be a successful modality for
the development of many small-molecule drugs. In recent years, small-molecule-induced
protein degradation has emerged as an orthogonal therapeutic strategy
that has the potential to expand the druggable target space. Focal
adhesion kinase (Fak) is a key player in tumor invasion and metastasis,
acting simultaneously as a kinase and a scaffold for several signaling
proteins. While previous efforts to modulate Fak activity were limited
to kinase inhibitors with low success in clinical studies, protein
degradation offers a possibility to simultaneously block Fak’s
kinase signaling and scaffolding capabilities. Here, we report the
development of a selective and potent Fak degrader, PROTAC-3, which outperforms a clinical candidate, defactinib, with respect
to Fak activation as well as Fak-mediated cell migration and invasion.
These results underline the potential that PROTACs offer in expanding
the druggable space and controlling protein functions that are not
easily addressed by traditional small-molecule therapeutics.
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small-molecule drugsFak activitysmall-molecule-induced protein degradationtumor invasionPROTACs offerprotein degradationprotein functionsdruggable spacedruggable target spacePROTAC-Mediated DegradationFak-mediated cell migrationsmall-molecule therapeuticsFak activationPROTAC -3Focal adhesion kinasekinase inhibitorsscaffolding capabilitiesKinase-Independent FunctionsFak degrader
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