Discovery of an Oral, Beyond-Rule-of-Five Mcl‐1 Protein−Protein Interaction Modulator with the Potential of Treating Hematological Malignancies.


In this paper, researchers from Janssen Pharmaceuticals were searching for a bespoke inhibitor of myeloid cell leukemia 1 (Mcl-1), which is among a family of proteins that regulate apoptosis, and is over-expressed in a number of hematological cancers and solid tumours. Mcl-1 inhibition requires the blocking of a protein-protein interaction (PPI), thus most of the existing inhibitors reside in the beyond-rule-of-five (bRo5) chemical space (see here for our perspective on bRo5), with molecular weight (Mw) > 600 Da, topological polar surface area (tPSA) > 120 Å2, and calculated logP (clog P) > 5. Due to some complex cardiotoxicity pathways related to Mcl-1 inhibition, the authors were searching for a “peak-shaped” in-vivo PK profile (high Cmax, relatively short half life) and incorporated human-induced pluripotent stem-cell-derived cardiomyocytes (hiPSC-CMs) into their assay cascade to assess and minimise cardiotoxicity while performing lead optimisation.

Design strategy included combining SAR elements that are already known and comprised of (1) macrocyclisation, (2) incorporation of rigidifying substituents and rings and (3) growing into new vectors enabled by structural insights. Studies were augmented by computational models, for example: an intramolecular H-Bond was predicted after fluorination of a vinylic C-H. This fluorination increased the Mcl-1 enzyme potency, but did not correspond to an improved enzyme-cell potency correlation compared with the nonfluorinated analogue – thus suggesting that permeability was not greatly impacted (MDCK-MDR1 assays turned out to be uninformative in this case). That aside, the lead compound achieved an astonishing oral bioavailability of 78%. For a compound with a MW of 770 g mol-1, a tPSA of 142 Å2 and an ePSA of 224 Å2 to achieve such a high bioavailability is impressive, and interesting. While it could be down to a combination of specific uptake mechanisms, traditional expectations and ADME predictions based on physical and calculated properties continue to be challenged by bRo5 compounds