Preface
The history of protein kinase inhibitors (PKI) is remarkable in many ways. Scientifically, as some 30 years ago, selective inhibition of protein kinases by ATP-sitedirected PKIs was considered as principally impossible, both due to the highly
conserved nature of this site and the high intracellular concentration of ATP. Now
we have several highly selective inhibitors for various kinases, and designing
selectivity is a daily practice for medicinal chemists in this field. Commercially,
PKIs are remarkable as well. 20 years after the launch of the first product, imatinib,
we have more than 60 registered drugs on the market with more than US$25 billion
annual sales worldwide. The future is bright as well, since new indications beside
cancer, e.g. inflammation, autoimmunity, and neurodegeneration have been
explored, new inhibition mechanisms as allosteric inhibitors, covalent inhibitors,
and substrate-specific inhibitors have showed up or are close to come – what’s next?
The pipeline of clinical candidates is full, more than 500 new chemical entities are in
clinical trials.
In such a dynamic field, a book is outdated even before it is published. Our goal
was therefore less to show the latest state of the art, but rather to focus on principles
of design and examples of successful implementation. A mix of authors from
industry and academia, old experts, and young talents will give us a broader view
from all sides.
We thank all who contributed to this book, the authors, the publisher, and MS. K.
Schmidt for language polishing and proofreading.
Tübingen, Germany
Stefan Laufer
December 2020
v
The history of protein kinase inhibitors (PKI) is remarkable in many ways. Scientifically, as some 30 years ago, selective inhibition of protein kinases by ATP-sitedirected PKIs was considered as principally impossible, both due to the highly
conserved nature of this site and the high intracellular concentration of ATP. Now
we have several highly selective inhibitors for various kinases, and designing
selectivity is a daily practice for medicinal chemists in this field. Commercially,
PKIs are remarkable as well. 20 years after the launch of the first product, imatinib,
we have more than 60 registered drugs on the market with more than US$25 billion
annual sales worldwide. The future is bright as well, since new indications beside
cancer, e.g. inflammation, autoimmunity, and neurodegeneration have been
explored, new inhibition mechanisms as allosteric inhibitors, covalent inhibitors,
and substrate-specific inhibitors have showed up or are close to come – what’s next?
The pipeline of clinical candidates is full, more than 500 new chemical entities are in
clinical trials.
In such a dynamic field, a book is outdated even before it is published. Our goal
was therefore less to show the latest state of the art, but rather to focus on principles
of design and examples of successful implementation. A mix of authors from
industry and academia, old experts, and young talents will give us a broader view
from all sides.
We thank all who contributed to this book, the authors, the publisher, and MS. K.
Schmidt for language polishing and proofreading.
Tübingen, Germany
Stefan Laufer
December 2020
v