Our place on a continuum

Earlier today, during a day trip to Merck’s Kellingworth site in New Jersey along with Drs. Andrew Roughton and Jeff Coull of Encycle Therapeutics (http://www.encycletherapeutics.com), I kept thinking about the ever-expanding breadth of molecules big pharma is going after these days. We are indeed living in interesting times. Merck, which has been a citadel of small molecule chemistry for a number of years, is one of the major companies actively pursuing therapeutics that have traditionally been outside their focus. It is comforting that a full arsenal of tools – small molecules, peptides, macrocycles, antibodies – are being routinely deployed in efforts to go after targets of ever-increasing complexity. On the New Jersey side, Dr. Yusheng Xiong (Director, Medicinal Chemistry) was our host during this visit. We had a chance to talk about a gamut of options to bear on Merck’s targets of interest (I hope I will be able to discuss this at some point on this blog). Some time ago I formulated a position that seems to resonate with our industry colleagues. In brief, I like to think about a continuum of molecular sizes that exist in our daily pursuits. The way I illustrate it in my talks is by showing the following graphic:


A protein of some significance (shown on the right) is usually our target, but the options we use range from small molecules to substantially larger macrocycles. The way I like to put this into perspective is to say that when we interrogate proteins with small molecules, we are drawn to the relative simplicity with which we can modulate enthalpic interactions. The middle ground in this continuum is occupied by macrocycles, which represent an intuitively clear connection to entropic penalties accrued in a protein/protein interaction. There indeed appears to be a certain entropy-centric “gut reaction” chemists have when they look at a macrocycle. This way of thinking becomes particularly meaningful when there is a need to “freeze” parts of a protein secondary structure.

I do think there is a conceptual continuum of sizes. I am also convinced that there is no need to be dogmatic about compartmentalizing oneself into a comfort zone in a narrow part of the spectrum. All options need to be deployed at the right moment. During our visit it was also great to interact with Tomi Sawyer of Merck, who was the head of chemistry at Aileron until not long ago (the stapled peptide company started by Greg Verdine). Tomi will be one of the lecturers at the American Peptide Society Meeting I am putting together with Ved Srivastava of GlaxoSmithKline (http://aps2015.org). I can’t wait to hear about Merck’s latest accomplishments.

Thank you, Yusheng, for a day full of insights!

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