Hello,

it is probably a reference to the chronology of release of the inhibitor - first-generation being ones that have less specificity and require higher doses for the intended effect, with more side-effects and off-target effects that eventually are identified and and eliminated or mitigated by later-released inhibitors of the same kinase.  In some cases as well, the side effects were so extreme that the original findings published using the inhibitor turn out to be completely wrong.

For instance - in MAP kinase circles, for many years the main inhibitor was the Parke-Davis compound PD98059.  This however, was replaced in the field by PD184352 that had certain advantages (I think also it was more soluble so easier to use) and could be referred to as a second generation inhibitor in this sense.

Worth also reading publications from people at the heart of this area of research over the past 35 years such as Philip Cohen, i.e. -

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1221339/

Thanks a lot Robin! This really helped.