dTAG-13 is a thalidomide-based PROTAC targeting mutant FKBP12F36V fusion proteins. dTAG-13 at concentration of 500nM could almost completely degrade the carboxy-terminal FKBP12F36V fusions in MV4;11-Cas9 cells post 1h. dTAG-13 inhibited cell proliferation of MV4;11 (Cas9+, ENL-FKBP12F36V–HA+) cells with IC50 value of 49.7nM post 72-hour treatment[1]. Treatment with 100nM for 4h selectively degraded FKBP12F36V in a CRBN-dependent manner in 293FTWT expressing FKBP12F36V. Also, dTAG-13 at concentration of 500nM could efficiently led a rapid degradation of a various nuclear and cytoplasmic FKBP12F36V fusion chimeras, including HDAC1-FKBP12F36V, MYC-FKBP12F36V, PLK1-FKBP12F36V, FKBP12F36V-EZH2, FKBP12F36V-KRASG12V, in MV4;11 cells expressing these fusion chimeras post 24-hour treatment. The degradation of FKBP12F36V-KRASG12V by dTAG-13 caused the decrease of pAkt-S473 and pMek-S221 in a time- and dose-dependent manner, exhibited an anti-proliferative effect on NIH/3T3 cells expressing FKBP12F36V-KRASG12V, as well as rapidly reversed the deregulated proteomic and transcriptional signaling program of transformed cells. Administration of dTAG-13 at dose of 25mg/kg effective degradation of FKBP12F36Vin vivo[2].
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