Discovery of novel coumarin derivatives as potent and orally bioavailable BRD4 inhibitors based on scaffold hopping

Abstract

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer, inflammation, obesity, and cardiovascular disease. Recently, the discovery of novel BRD4 inhibitors has garnered substantial interest. Starting from scaffold hopping of the reported compound dihydroquinazolinone (PFI-1), a series of coumarin derivatives were designed and synthesised as a new chemotype of BRD4 inhibitors. Interestingly, the representative compounds 13 exhibited potent BRD4 binding affinity and cell proliferation inhibitory activity, and especially displayed a favourable PK profile with high oral bioavailability (F = 49.38%) and metabolic stability (T_1/2 = 4.2 h), meaningfully making it as a promising lead compound for further drug development.

Keywords: BRD4 bromodomain; Rational drug design; biological evaluation; synthesis.

Graphical abstract

Figure 1.

Representative, previously reported bromodomain inhibitors.

Figure 2.

Structures of approved coumarin-containing drugs.

Figure 3.

(A) Crystal structure of BRD4 BD1 bound to PFI-1 (PDB ID: 4E96). The protein is shown as a light gray cartoon and PFI-1 is shown as sticks (carbon atoms in green, oxygens in red, nitrogens in blue and sulfurs in brown). (B) Design concept of new BRD4 inhibitors. (C) The docking model of 1 with BRD4 BD1 (carbon atoms in cyan). (D) Superimposition of PFI-1 (green carbon atoms) and 1 (cyan carbon atoms) in their putative bioactive conformations.

Figure 4.

The design and synthesis of reversed sulfonamide compound 17.

Figure 5.

The docking model (PDB ID: 4E96) of 13 with BRD4 BD1 (carbon atoms in blue). Water molecule is shown as purple sphere, and the hydrogen bonds are denoted by gold dash lines.

Figure 6.

Dose–response curves of 13 in incubation with cancer cell lines (mean ± SD, n = 3).

Figure 7.

Effect of 13 on A549, HepG2, PANC-1 and SGC-7901 cells morphology. Cells after treating with 13 under relevant concentrations for 24 h were observed by invert/phase contrast microscopy.

Figure 8.

The plasma concentration-time curve of 13.

Scheme 1.

The synthetic route of compounds. Reagents and conditions: (a) HNO₃/H₂SO₄; (b) SnCl₂/HCl; (c) pyridine, sulphuryl chloride, rt.