1 Introduction
It is estimated that 5% of the human genome is dedicated to protein phosphorylation.
518 different human kinases have been identified and clustered in sub-groups
depending on substrate specificity and sequence similarity, but overall these
enzymes catalyze the same biochemical reaction, the transfer of a phosphate group
to a serine, threonine, or tyrosine residue [1]. From a pharmaceutical standpoint,
there is huge evidence that kinase activities are deregulated in a broad range of
diseases (cancer, inflammation, Parkinson, etc.) (https://www.cellsignal.com/con
tents/resources-reference-tables/kinase-disease-associations/science-tables-kinasedisease) which has triggered over the last decades a massive interest in identifying
and developing selective kinase inhibitors.
Cancer treatment is definitively the most important therapeutic domain where
kinases inhibitors have found their application, and today approximately 50 small
molecular weight kinase drugs have received marketing approval by the FDA, in
addition to a dozen of monoclonal antibodies directed mainly against the human
epidermal growth factor receptor kinase family (EGFR, HER2) [2, 3].
The first generation of marketed drugs (Gleevec, Sutent, Sprycel, etc.) [4]
exhibited multi-kinase inhibition profiles, supporting the paradigm that better efficacy would be achieved by multi-cellular pathway blockade and giving the opportunity to register the same drug in different indications (e.g., Gleevec launched in
2001 for the treatment of patients with Philadelphia chromosome-positive chronic
myeloid leukemia (CML) and in 2002 for the treatment of patients with Kit-positive
unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST)) [5].
The development of the targeted therapy paradigm in oncology [6, 7] as well as
the clinical demand for much better tolerated treatments has conducted research
programs in pharmaceutical companies towards the discovery of selective to exquisite kinase inhibitors [8–10].
Successful development of drugs targeting specific deregulated cellular signaling
pathways via selective inhibition of one targeted kinase (e.g., MEK) [11] or of
oncogenic mutants (e.g., EGFR DM, V600E BRAF) [12] has been achieved recently
[13, 14].
However, in the 1990s, when the first 3D crystal structure of a kinase (PKA) [15]
was reported, a largely believed myth emerged that it would be impossible to
develop selective and potent protein or lipid kinase inhibitors by targeting the ATP
binding site due to a priori lack of specificity and high level of sequence similarity
across the kinome. In mid-2019, more than 6,000 human protein kinases and more
than 160 human lipid kinase 3D structures were deposited in the PDB (https://www.
rcsb.org/). Thorough analyses of apo-structures vs ATP analog or ligand bound
co-structures have revealed general modes of kinase activation [16, 17], including
those behind oncogenic mutations [18–20], as well as subtle specific interactions in
the active site and several preferred conformations (DFG-in, DFG-out, and α helixout) [21, 22].
96
L. Schio and H. Minoux
It is estimated that 5% of the human genome is dedicated to protein phosphorylation.
518 different human kinases have been identified and clustered in sub-groups
depending on substrate specificity and sequence similarity, but overall these
enzymes catalyze the same biochemical reaction, the transfer of a phosphate group
to a serine, threonine, or tyrosine residue [1]. From a pharmaceutical standpoint,
there is huge evidence that kinase activities are deregulated in a broad range of
diseases (cancer, inflammation, Parkinson, etc.) (https://www.cellsignal.com/con
tents/resources-reference-tables/kinase-disease-associations/science-tables-kinasedisease) which has triggered over the last decades a massive interest in identifying
and developing selective kinase inhibitors.
Cancer treatment is definitively the most important therapeutic domain where
kinases inhibitors have found their application, and today approximately 50 small
molecular weight kinase drugs have received marketing approval by the FDA, in
addition to a dozen of monoclonal antibodies directed mainly against the human
epidermal growth factor receptor kinase family (EGFR, HER2) [2, 3].
The first generation of marketed drugs (Gleevec, Sutent, Sprycel, etc.) [4]
exhibited multi-kinase inhibition profiles, supporting the paradigm that better efficacy would be achieved by multi-cellular pathway blockade and giving the opportunity to register the same drug in different indications (e.g., Gleevec launched in
2001 for the treatment of patients with Philadelphia chromosome-positive chronic
myeloid leukemia (CML) and in 2002 for the treatment of patients with Kit-positive
unresectable and/or metastatic malignant gastrointestinal stromal tumor (GIST)) [5].
The development of the targeted therapy paradigm in oncology [6, 7] as well as
the clinical demand for much better tolerated treatments has conducted research
programs in pharmaceutical companies towards the discovery of selective to exquisite kinase inhibitors [8–10].
Successful development of drugs targeting specific deregulated cellular signaling
pathways via selective inhibition of one targeted kinase (e.g., MEK) [11] or of
oncogenic mutants (e.g., EGFR DM, V600E BRAF) [12] has been achieved recently
[13, 14].
However, in the 1990s, when the first 3D crystal structure of a kinase (PKA) [15]
was reported, a largely believed myth emerged that it would be impossible to
develop selective and potent protein or lipid kinase inhibitors by targeting the ATP
binding site due to a priori lack of specificity and high level of sequence similarity
across the kinome. In mid-2019, more than 6,000 human protein kinases and more
than 160 human lipid kinase 3D structures were deposited in the PDB (https://www.
rcsb.org/). Thorough analyses of apo-structures vs ATP analog or ligand bound
co-structures have revealed general modes of kinase activation [16, 17], including
those behind oncogenic mutations [18–20], as well as subtle specific interactions in
the active site and several preferred conformations (DFG-in, DFG-out, and α helixout) [21, 22].
96
L. Schio and H. Minoux