Chiral Analogues of PFI-1 as BET Inhibitors and Their Functional Role in Myeloid Malignancies
Though the influence of stereochemistry is well established within the context of medicinal chemistry, most stereocenters typically reside at C-based centers, and relatively few enantiopure drugs bear stereocenters at heteroatom-based centers. In this issue, Bolm, Rossetti, and co-workers (DOI: 10.1021/acsmedchemlett.9b00625) explore innovative BET BRD4 inhibitors that bear S-chiral stereocenters. Specifically, using a previously explored lead molecule, PFI-1, replacement of the commonly used achiral sulfonamide group with an S-chiral sulfoxime group delivered a racemic inhibitor with antiproliferative activity in HEL and Molm-14 cell lines. Separation of the enantiomers identified the (S)-enantiomer as having inhibitory activity, and further characterization of bromodomain selectivity using thermal shift assays demonstrated modest selectivity for BRD-2/4 relative to the parent. Further characterization using cell-cycle progression assays, viability, and apoptosis (via PARP cleavage) further supported BRD4 inhibition. Computational modeling of the BRD4 in complex with the (S)-enantiopure sulfoxime analog indicated key ligand–protein differences imparted by the sufonamide → sulfoxime replacement, including changes in hybridization of the N that perturb the basicity of lone pair electrons that in turn influence solvation and hydrophobicity, as well as conformational considerations imparted by the S–N bond relative to the S=N bond. Overall, this instructive example should help medicinal chemists strategically exploit this emerging functional group in other campaigns.
Discovery of A-1331852, a First-in-Class, Potent, and Orally Bioavailable BCL-XL Inhibitor
The antiapoptotic BCL-2 family of proteins is an important class of drug targets for treating hematological malignancies and solid tumors through blocking protein–protein interactions with BH3 domains. Both monotherapy and combination therapy with chemotherapeutics have proven effective. ABT-263 (Navitoclax), which targets BCL-2, BCL-XL, and BCL-W, shows strong antitumor activity for lymphoid diseases but significant BCL-XL-dependent thrombocytopenia. This discrepancy led to development of the BCL-2 selective inhibitor ABT-199 (Venetoclax), which is well-tolerated for treating chronic lymphocytic leukemia. Alternatively, in treating solid tumors with Navitoclax, BCL-2 dependent dose-limiting neutropenia occurs. In this Featured Letter (DOI: 10.1021/acsmedchemlett.9b00568), Judd and co-workers report the structure-based design optimization story for the BCL-XL selective inhibitor A-1331852. Starting from a lead scaffold, the authors systematically optimize a key pharmacophore and reduce compound flexibility through incorporation of heterocyclic linkers to generate a second generation lead with improved pharmacokinetic properties. An unexpected finding is the increased plasticity of the P4 pocket of BCL-XL which allows for replacement of a key aromatic group found in Navitoclax for large sp3-rich fragments. The authors ultimately arrive at A-1331852, with picomolar binding affinity, high BCL-XL selectivity, and unprecedented cell activity. In vivo tumor models of human colorectal cancer using A-1331852 as a monotherapy or in combination therapy with topoisomerase I inhibitors demonstrates a highly effective antitumor therapy. Thus, A-1331852 represents an exciting starting point for initiating a BCL-XL specific drug discovery program and further exploring BCL-2 family protein biology. A key takeaway from this structure-based design development story is that significant plasticity of protein–protein interaction interfaces can be exploited for selective inhibitor design.
Substituted Azabicyclo[2.2.1]heptanes as Selective Orexin-1 Antagonists: Discovery of JNJ-54717793
The origin GPCRs (OX1R and OX2R) regulate a variety of neurological functions including sleep/wake cycles, circadian rhythms, metabolism, reward behavior, and anxiety and stress responses, making them intriguing targets for medicinal chemists. To probe the pharmacology and to exploit the therapeutic utility of these targets, selective modulators are necessary, though for OX1R, most pharmacological studies have exploit knockout animal, siRNA experiments, or a tool compound, SB-334867, the latter of which lacks sufficient physicochemical properties and selectivity to properly evaluate the druggability of this target. In this issue, Shireman and co-workers from Janssen report the medicinal chemistry optimization and preclinical development of JNJ-54717793 (DOI: 10.1021/acsmedchemlett.0c00085), an orally bioavailable, brain penetrant, OX1R antagonist. Starting from a nonselective lead molecule identified from an OR2X program, systematic lead optimization delivered a >40-fold selective OR1X antagonist with appropriate properties to engage OX1R with appropriate occupancy using an ex vivo receptor binding autoradiography assay (rat) to evaluate target engagement. Further characterization of physicochemical and in vitro ADME profiling identified the lead candidate that provided good pharmacokinetics across four species and that predicted reasonable doses for human QD dosing. Further characterization of in vivo generated metabolites, P450 profiling, and 5–7 day repeat toxicokinetic studies indicated that JNJ-54717793 displayed an excellent profile for further development and exploration of OX1R pharmacology.
