Are We There Yet? Applying Thermodynamic and Kinetic Profiling on Embryonic Ectoderm Development (EED) Hit-to-Lead Program

It is advocated that kinetic and thermodynamic profiling of bioactive compounds should be incorporated and utilized as complementary tools for hit and lead optimizations in drug discovery. To assess their applications in the EED hit-to-lead optimization process, large amount of thermodynamic and kinetic data were collected and analyzed via isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR), respectively. Slower dissociation rates (<i>k</i>_off) of the lead compounds were observed as the program progressed. Analysis of the kinetic data indicated that compound cellular activity correlated with both <i>K</i>_i and <i>k</i>_off. Our analysis revealed that ITC data should be interpreted in the context of chiral purity of the compounds. The thermodynamic signatures of the EED amino­pyrrolidine compounds were found to be mainly enthalpy driven with improved enthalpic contributions as the program progressed. Our study also demonstrated that significant challenges still exist in utilizing kinetic and thermodynamic parameters for hit selection

Discovery of <i>N</i>‑(4-(2,4-Difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro‑1<i>H</i>‑pyrrolo[2,3‑<i>c</i>]pyridin-4-yl)phenyl)ethanesulfonamide (ABBV-075/Mivebresib), a Potent and Orally Available Bromodomain and Extraterminal Domain (BET) Family Bromodomain Inhibitor

The development of bromodomain and extraterminal domain (BET) bromodomain inhibitors and their examination in clinical studies, particularly in oncology settings, has garnered substantial recent interest. An effort to generate novel BET bromodomain inhibitors with excellent potency and drug metabolism and pharmacokinetics (DMPK) properties was initiated based upon elaboration of a simple pyridone core. Efforts to develop a bidentate interaction with a critical asparagine residue resulted in the incorporation of a pyrrolopyridone core, which improved potency by 9–19-fold. Additional structure–activity relationship (SAR) efforts aimed both at increasing potency and improving pharmacokinetic properties led to the discovery of the clinical candidate <b>63</b> (ABBV-075/mivebresib), which demonstrates excellent potency in biochemical and cellular assays, advantageous exposures and half-life both in animal models and in humans, and in vivo efficacy in mouse models of cancer progression and inflammation