The impressive recent traction received by Abbvie’s Venetoclax is the subject of today’s post. Dr. G. Poda of OICR brought this molecule to my attention. Venetoclax constitutes a notable addition to the growing list of small molecule inhibitors that target protein-protein interactions. The compound just got the breakthrough therapy designation from the FDA, which speeds up the regulatory review process (http://www.dddmag.com/news/2015/05/abbvie-receives-breakthrough-designation-cancer-drug). A potent inhibitor of the B-cell lymphoma-2 (BCL-2) protein, Venetoclax shows once again that small molecules (more on that later…) can inhibit fairly extended protein interfaces. Below I am showing a view of the co-crystal structure between BCL-2 and one of Venetoclax’s close relatives – Navitoclax (pdb ID 4LVT). The last 10 years have witnesses a ton of research aimed at the BCL-2 family of proteins with all manner of synthetic tools thrown at this challenge. You probably saw stapled peptides developed by Verdine and Walensky. Abbvie’s compound now nicely fills the coveted hydrophobic patch while showing clinical efficacy.

If there were such a thing as chemical aesthetics in drug design, Venetoclax would probably not get the top prize. I am sorry, but this is one ugly molecule with all sorts of weird overhangs. Some of the structural features remind me of the mess the construction crew left in our basement two weeks ago. Those guys did a decent job in terms of the ultimate functionality we desired, but we did have to always watch out that the never-ending adjustments would not take a toll on the aesthetics.

Coming back to Venetoclax, calling it a small molecule is a stretch. Despite all of this, I am drawn to this structure, no matter how clunky it may look. Venetoclax is a nice way to showcase the merit of elongated molecules, which I have been developing quite an interest in. One of these days I will write a paper dedicated to inhibitors that look like sticks. I do think they occupy an interesting niche (as do macrocycles, but those serve a more “circular” purpose).