Biological Activity and Structural Biology of Current KAT6A Inhibitor Chemotypes.

Area of Science:

• Biochemistry and Chemical Biology
• Medicinal Chemistry
• Cancer Biology

Background:

• Lysine acetyltransferases (KATs) regulate biological processes via acetylation, utilizing acetyl-CoA.
• KAT6A, a MYST domain histone acetyltransferase (HAT), was historically considered undruggable.
• Recent discovery of KAT6A inhibitors with in vivo activity has spurred significant oncology research interest.

Purpose of the Study:

• To experimentally evaluate representative KAT6A inhibitor chemotypes.
• To explore structure-activity relationships (SAR) for potency, selectivity, and cellular effects.
• To report novel KAT6A inhibitor subclasses and their preclinical profiles.

Main Methods:

• Resynthesis and comparative biochemical and cellular assays of known KAT6A inhibitor chemotypes.
• Structural biology, including co-crystal structures of novel inhibitors.
• Pharmacokinetic (PK), in vivo activity, and toxicology assessments.

Main Results:

• Benchmarking of key compounds across different KAT6A inhibitor chemotypes.
• Identification and characterization of novel acylsulfonohydrazide analogues.
• Discovery and structural elucidation of a new fused [1,2,4]thiadiazine KAT6A inhibitor subclass.

Conclusions:

• The study provides a comprehensive evaluation of KAT6A inhibitors, including novel chemical matter.
• Detailed SAR, biochemical, cellular, and in vivo data support the therapeutic potential of KAT6A inhibition in oncology.
• The newly identified thiadiazine subclass represents a promising avenue for future drug development against KAT6A.