A novel 7-phenoxy-benzimidazole derivative as a potent and orally available BRD4 inhibitor for the treatment of melanoma.

The bromodomain-containing protein 4 (BRD4), which is a key epigenetic regulator in cancer, has emerged as an attractive target for the treatment of melanoma. In this study, we investigate 7-phenoxy-benzimidazole derivative 12, which is a novel BRD4 inhibitor for the treatment of melanoma, by performing scaffold hopping on the previously reported benzimidazole derivative 1. Despite their good oral and intravenous exposure, the compounds obtained by modifying derivate 1 exhibit mutagenicity, which was confirmed by the positive Ames test results. Based on our hypothesis that the cause of the Ames test positivity is the metabolic intermediates generated from those chemical series, we implemented a scaffold hopping strategy to avoid the N-benzyl moiety by relocating the substituent groups to preserve the essential interaction. Based on this strategy, we successfully obtained compound 12; the Ames test results of this compound were negative. Notably, compound 12 not only exhibited a favorable pharmacokinetic (PK) profile but also significant tumor growth inhibition in a mouse melanoma xenograft model, indicating its potential as a therapeutic agent for the treatment of melanoma.

Discovery of a potent, orally available tricyclic derivative as a novel BRD4 inhibitor for melanoma.

The epigenetic regulation of the protein bromodomain-containing protein 4 (BRD4) has emerged as a compelling target for cancer treatment. In this study, we outline the discovery of a novel BRD4 inhibitor for melanoma therapy. Our initial finding was that benzimidazole derivative 1, sourced from our library, was a powerful BRD4 inhibitor. However, it exhibited a poor pharmacokinetic (PK) profile. To address this, we conducted a scaffold-hopping procedure with derivative 1, which resulted in the creation of benzimidazolinone derivative 5. This new derivative displayed an improved PK profile. To further enhance the BRD4 inhibitory activity, we attempted to introduce hydrogen bond acceptors. This indeed improved the activity, but at the cost of decreased membrane permeability. Our search for a potent inhibitor with desirable permeability led to the development of tricyclic 18. This compound demonstrated powerful inhibitory activity and a favorable PK profile. More significantly, tricyclic 18 showed antitumor efficacy in a mouse melanoma xenograft model, suggesting that it holds potential as a therapeutic agent for melanoma treatment.

Effects of episodic slow slip on seismicity and stress near a subduction-zone megathrust.

Slow slip phenomena deep in subduction zones reveal cyclic processes downdip of locked megathrusts. Here we analyze seismicity within a subducting oceanic slab, spanning ~50 major deep slow slip with tremor episodes over 17 years. Changes in rate, b-values, and stress orientations of in-slab seismicity are temporally associated with the episodes. Furthermore, although stress orientations in the slab below these slow slips may rotate slightly, in-slab orientations 20-50 km updip from there rotate farther, suggesting that previously-unrecognized transient slow slip occurs on the plate interface updip. We infer that fluid pressure propagates from slab to interface, promoting episodes of slow slip, which break mineral seals, allowing the pressure to propagate tens of km further updip along the interface where it promotes transient slow slips. The proposed methodology, based primarily on in-slab seismicity, may help monitor plate boundary conditions and slow slip phenomena, which can signal the beginning stages of megathrust earthquakes.