Design and Discovery of Pyridazinone-Based MAT2A Inhibitors Targeting MTAP-Deficient Cancers

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• MAT2A inhibition is a promising synthetic strategy for cancers with MTAP deletions.
• Existing inhibitors require optimization for potency and therapeutic application.

Purpose of the Study:

• To design and optimize novel pyridazinone-based MAT2A inhibitors.
• To identify a lead compound for further preclinical development in MTAP-deficient cancers.

Main Methods:

• Ring-opening strategy from AGI-41998 to generate pyridazinone analogs.
• Iterative structure-activity relationship (SAR) studies to identify lead compound 33.
• In vitro enzymatic and cellular assays (IC50, GI50), in vivo pharmacokinetic and efficacy studies in xenograft models, and mechanistic studies (SAM and sDMA levels).

Main Results:

• Compound 33 exhibited potent MAT2A inhibition (IC50 = 17.5 nM) and strong cellular activity (GI50 = 0.76 μM) in HCT-116 MTAP KO cells.
• Compound 33 maintained high potency in MTAP-naturally deficient cancer cell lines.
• In vivo studies showed favorable pharmacokinetics, significant antitumor efficacy in NCI-H838 xenografts with minimal toxicity, and reduced SAM/sDMA levels.

Conclusions:

• Pyridazinone serves as a privileged scaffold for developing MAT2A inhibitors.
• Compound 33 is a compelling lead candidate for further preclinical investigation in MTAP-deleted cancers.
• MAT2A inhibition effectively reduces SAM and sDMA, offering a viable therapeutic avenue.