Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing...

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• The ATPase ATAD2 is overexpressed in various cancers, correlating with poor patient prognosis.
• ATAD2 acts as a cofactor for transcription factors like MYC and the androgen receptor.
• ATAD2 possesses an ATPase domain for chromatin remodeling and a bromodomain for interacting with acetylated histones.

Purpose of the Study:

• To develop selective, cell-permeable pharmacological probes for dissecting ATAD2's functional domains.
• To identify lead compounds for ATAD2 bromodomain inhibitor development.

Main Methods:

• Structure-guided fragment-based drug design approach.
• In silico evaluation of bromodomain 3D structures.
• Identification and optimization of fragment hits with M_r < 200.

Main Results:

• Successfully identified fragment hits for the ATAD2 bromodomain.
• Established productive structure-activity relationships for lead compounds.
• Achieved selectivity for the ATAD2 bromodomain over BRD4 through structure-guided design.

Conclusions:

• The ATAD2 bromodomain can accommodate small fragment molecules.
• Structure-guided design is effective for developing selective ATAD2 bromodomain inhibitors.
• These findings pave the way for novel cancer therapeutics targeting ATAD2.