AZD6738 decreases intraocular pressure and inhibits fibrotic response in trabecular meshwork through CHK1/P53 pathway

Area of Science:

• Ophthalmology
• Pharmacology
• Cell Biology

Background:

• Glaucoma is characterized by elevated intraocular pressure (IOP) and fibrosis in the trabecular meshwork (TM).
• Current treatments aim to reduce IOP but often have limitations.

Purpose of the Study:

• To investigate the efficacy of AZD6738 (Ceralasertib), an ATR kinase inhibitor, in reducing IOP and inhibiting TM fibrosis.
• To elucidate the molecular mechanisms underlying AZD6738's effects on TM cells.

Main Methods:

• Utilized a mice TGF-β2-induced high IOP model.
• Treated human trabecular meshwork cells (HTMCs) with TGF-β1 to induce fibrotic responses.
• Assessed IOP, TM hyperplasia, collagen production, ECM remodeling, cell viability, migration, and molecular markers via CHK1/P53 pathway analysis.
• Preliminary safety evaluation for topical ophthalmic use.

Main Results:

• AZD6738 significantly decreased IOP in the mouse model.
• AZD6738 inhibited TGF-β2-induced TM hyperplasia, collagen production, fibrosis, and ECM remodeling by downregulating checkpoint kinase 1 (CHK1).
• AZD6738 reduced HTMC viability and migration, inhibited fibrosis-related factors (FN, α-SMA, LAMB1, MMP2, MMP9, COL1, COL4), altered cytoskeleton, and reduced nitric oxide production via the CHK1/P53 pathway.

Conclusions:

• AZD6738 demonstrates potent anti-fibrotic effects in the TM and reduces IOP.
• The drug acts through the CHK1/P53 pathway, impacting aqueous humor dynamics.
• AZD6738 shows potential as a novel therapeutic agent for glaucoma treatment.