FKBP12 PROTAC RC32(Tsinghua University)

In this study, using a PROTAC mol. RC32 to promote FKBP12 degradation, we achieved BMP signaling activation and hepcidin upregulation as good as using classical FKBP12 binding mols. FK506 and Rapamycin in vitro.In mice, RC32 transiently elevated serum hepcidin and reduced serum iron levels, in a manner comparable to FK506.Compared to FK506 or Rapamycin with instinct side-effects, at least in vitro, RC32 does not inhibit mTOR or Calcineurin and shows no immunosuppression activity.Derivatives of FKBP12 binding mols. that lack immunosuppression activity were developed and their capacity in hepcidin regulation should also be tested in the future.Our study, therefore, suggested that PROTAC-mediated FKBP12 degradation could be a novel and safe approach to treat iron overload diseases resulting from low hepcidin.FKBP12 associates with the BMP receptor and prevents uncontrolled BMP signaling activation.Activation of BMP signaling by releasing FKBP12 has signi fi cant applications in BMP signaling de fi ciency-related diseases such as Idiopathic pulmonary arterial hypertension (IPAH), wound healing, or cancer metastasis.In all these cases, PROTAC-mediated FKBP12 degradation could serve as an alternative approach.