ATAD2 in cancer: a pharmacologically challenging but tractable target

ABSTRACT

Introduction: ATAD2 protein is an emerging oncogene that has strongly been linked to the etiology of multiple advanced human cancers. Therapeutically, despite the fact that genetic suppression/knockdown studies have validated it as a compelling drug target for future therapeutic development, recent druggability assessment data suggest that direct targeting of ATAD2’s bromodomain (BRD) may be a very challenging task. ATAD2’s BRD has been predicted as a ‘difficult to drug’ or ‘least druggable’ target due to the concern that its binding pocket, and the areas around it, seem to be unfeasible for ligand binding.

Areas covered: In this review, after shedding light on the multifaceted roles of ATAD2 in normal physiology as well as in cancer-etiology, we discuss technical challenges rendered by ATAD2’s BRD active site and the recent drug discovery efforts to find small molecule inhibitors against it.

Expert opinion: The identification of a novel low-nanomolar semi-permeable chemical probe against ATAD2’s BRD by recent drug discovery campaign has demonstrated it to be a pharmacologically tractable target. Nevertheless, the development of high quality bioavailable inhibitors against ATAD2 is still a pending task. Moreover, ATAD2 may also potentially be utilized as a promising target for future development of RNAi-based therapy to treat cancers.

KEYWORDS:

• ATAD2
• AAA ATPase
• BRD
• cancer
• druggable
• ligandability
• metastasis
• siRNA

Article highlights

• ATAD2 is an emerging oncogene, which is aberrantly overexpressed in multiple advanced human cancers

• Genetic knockdown studies have validated ATAD2 as a compelling drug target for future therapeutic development against cancer

• ATAD2’s bromodomain has earned the reputation of a ‘difficult to drug’ or ‘least druggable’ target among the bromodomain target class

• Recent drug discovery campaign by GlaxoSmithKline has demonstrated ATAD2’s bromodomain to be a pharmacologically tractable target

• The development of high quality bioavailable inhibitors against ATAD2 is still a pending task

This box summarizes key points contained in the article.

Declaration of Interest

M. Hussain is sponsored by CAS-TWAS President’s Fellowship for international PhD students. Y. Zhou acknowledges financial support from the China Scholarship Council for his PhD studies. H. M. Adnan Hameed is sponsored by UCAS Fellowship for international PhD students. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.