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

Abstract

Avoidance of apoptosis is critical for the development and sustained growth of tumors. The pro-survival protein myeloid cell leukemia 1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family of proteins which is overexpressed in many cancers. Upregulation of Mcl-1 in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Therefore, pharmacological inhibition of Mcl-1 is regarded as an attractive approach to treating relapsed or refractory malignancies. Herein, we disclose the design, synthesis, optimization, and early preclinical evaluation of a potent and selective small-molecule inhibitor of Mcl-1. Our exploratory design tactics focused on structural modifications which improve the potency and physicochemical properties of the inhibitor while minimizing the risk of functional cardiotoxicity. Despite being in the "non-Lipinski" beyond-Rule-of-Five property space, the developed compound benefits from exquisite oral bioavailability in vivo and induces potent pharmacodynamic inhibition of Mcl-1 in a mouse xenograft model.

Development of Potent Mcl-1 Inhibitors: Structural Investigations on Macrocycles Originating from a DNA-Encoded Chemical Library Screen

“…A regularly reported feature of this part of the Mcl-1 protein is the potential for forming an extended “P1′-pocket”. Many of the reported Mcl-1 inhibitors fill this induced-fit pocket; , however, 1 does not occupy this region and the inducible pocket appears to be collapsed. To further investigate the exact nature of the P1/P1’ pocket we superimposed the crystal structure with that of “Compound-60” (Figure ) from Fesik and co-workers, the molecular structure of which is depicted in Figure .…”

“…The phenylglycine side chain appears to partially occupy a small lipophilic den in the protein surface, formed by valines 216, 220, 265, and glycine 262, explaining why the Phg-epimer ( 18 ) lost much of its potency. The phenylglycine carbonyl forms an important H-bond interaction with Asp263, which is observed in nearly all reported Mcl-1 inhibitors, albeit usually in a salt bridge . Additionally, the same carbonyl forms a much less common interaction with the side chain of Asn260.…”

“…In the Mcl-1 complex structure (Figure ), compound 1 binds to the BH3-helix binding groove, , similarly to most reported Mcl-1 inhibitors, including those depicted in Figure . The macrocyclic compound occupies all of the most commonly found binding pockets, often designated as P1–4, as recently summarized in detail by Romanov-Michailidis, Hsiao et al . The peptidic Phe-Phg segment occupies the P4-area, with the phenylalanine side chain lying on top of Gly262 and wedged against a lipophilic wall formed by Phe318/319.…”

“…In 2020/2021, similar tetrahydronaphthalene-containing macrocyclic inhibitors were disclosed by both Gilead and Prelude Therapeutics, however with distinct differences in either the backbone structure or the decoration pattern. , Finally, linear DNA-encoded chemical library (DEL)-based screening hits that were subsequently macrocyclized have been described AstraZeneca and X-Chem in 2017 . Very recently, Janssen published their extensive work on two macrocyclic inhibitor series, based on the previously described indole carboxylic acid , and spirocyclic tetrahydronaphthalene cores, exemplified by JNJ-4355 and “Compound 28” in Figure , respectively.…”

Defluoroalkylation of gem-Difluoroalkenes with Alcohols via C–F/C–H Coupling

“…Recently, we developed a series of defluorofunctionalization reactions of multifluorinated substrates, , including the defluoroalkylations of polyfluoroarenes with alcohols through Lewis-acid-promoted C–H/C–F bond coupling under visible-light irradiations via a radical addition pathway (Scheme b) . Considering the low cost of alcohols and the wide application of α-fluoroalkenyl alcohol derivatives as bioactive compounds, herein we assumed that the coupling of alcohol α-C–H and C–F bonds from gem -difluoroalkenes might occur utilizing similar strategies to deliver α-fluoroalkenyl alcohol products. Notably, the redox properties of polyfluoroarenes and gem -difluoroalkenes are distinctive, suggesting the different radical involving pathways.…”