Hit to lead

Published on September 23, 2013   53 min

A selection of talks on Pharmaceutical Sciences

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Hello, my name is Mike Rafferty and the topic of my lecture is on early drug discovery activity known as Hit to Lead. Before we get into the subject matter, I would like to briefly introduce myself.
I was trained as a medicinal chemist at the University of Kansas and devoted essentially all of my professional career to pharmaceutical drug discovery and early development, mostly with large pharmaceutical companies. A few years ago, I returned to Kansas where I now hold an adjunct professor appointment in the department from which I graduated and I teach drug discovery practices in the graduate program, including the present topic.
On this slide, you will find a list of publications that I considered to be important in putting together this lecture. Most, if not all, of these references will be cited elsewhere in my presentation. I can highly recommend any or all of these papers to anyone who is interested in drug discovery and particularly in early-stage medicinal chemistry.
Here is what I'll be covering today. After a brief review of the drug discovery process and a definition of what I mean by Hit to Lead, I would then like to discuss the topic of hits, where they come from, how one executes the all-important process of picking the best hit among the available candidates to start a medicinal chemistry campaign.
What is Hit to Lead? Any drug discovery project must mature through at least three stages en route to the ultimate goal, which is the nomination of a development candidate. The Hit to Lead stage is the first point of engagement of chemistry with the project and really represents a transition between what was a biology project that has now evolved into a chemistry challenge. Just as a mutational defect in a monarch butterfly egg can compromise the whole process of maturation to a beautiful adult, beginning any project with a poor-quality hit is a recipe for failure by presenting often insurmountable problems for the chemist. In my opinion, hit selection is probably the most important decision that will be made over the course of the entire discovery project, and in a few minutes, we will talk about what goes into this decision. I include a quote taken from a review by Michael Hahn at GSK, which I think is a pretty good description of the ride that most drug discovery projects take en route to a candidate nomination process, that can be both exhilarating and frustrating.