Abstract
BRD2, BRD3, and BRD4 are members of the BET family of bromodomain inhibitors that have received intense current interest as novel treatments for cancer. The BET proteins function as epigenetic modulators that recognize specifically marked regions of histones and thereby influence gene transcription. Numerous highly potent, highly selective BET inhibitors have emerged and some (e.g. IBET-762) have advanced to clinical trials. We aimed to develop BET inhibitors as drug for untreatable forms of brain cancer including GBM (glioblastoma multiforme) and metastatic brain cancer. Unfortunately, we found that they are poorly suited as drugs for any indications that require high CNS drug exposure because they have high susceptibility to efflux transporters and low passive cellular permeability. To improve CNS penetration, we employed a structure-based design approach that involved (1) disrupting key transporter pharmacophore points and (2) altering the physical properties to improve cellular permeability. In this manner we have identified EP11313 which has strong potency (BRD4 IC50 7 nM), low efflux (ER <2), high passive cellular permeability (Papp 13.3 × 10−6 cm/s), moderate oral bioavailability in mouse (59%) and high CNS exposure. EP11313 (after daily drug administration for 3 weeks) shows antiproliferative effects in TMZ-resistant cancer patient stem cell lines and dose-dependent tumor reduction in nu/nu mice that were centrally transplanted with luciferase-expressing GBM cell xenografts.