series of intermediate water molecules (Fig. 20a), whereas in PI3Kδ, the equivalent
residue is Asn836, which is also located at $7 Å from the ligand and connected to
Water1 via a similar network (Fig. 20b). Due to a more efficient charge transfer
realized with Asp856 compared to the neutral Asn836, translated into more H-bonds
to Water1, and shortest distances within the water network, PI3Kβ better tolerates
the destabilizing influences of the methyl group in the (S)-configuration than PI3Kδ,
which encloses Water1 in a more hydrophobic environment, leading to the observed
selectivity. Interestingly, this hypothesis reconnects to the privileged residue analysis [23] as Asp856 is one of them.
Compound (S)-27 became eventually SAR301260, a clinical development candidate tested in PTEN-deficient cancer patients [84].
6 Conclusions
Through the aforementioned projects which have been described, it was possible to
identify and design very selective kinase inhibitors and dial out off-target affinity vs
close kinase neighbors. If state-of-the art technologies were applied during the
course of those projects (in biophysics, in modeling, etc.), serendipity in screens or
in chemistry remained a significant contributor to these successful drug discovery
programs. Moreover, exquisite selectivity was in certain circumstances rationalized
a posteriori rather than guided (e.g., PI3Kβ). Still, the key protein elements or ligand
properties which were identified to obtain and improve selectivity in one case or
another have served subsequent kinase projects in our group and knowledge
increased by experience for better efficiency. It is worth mentioning that other
types of mechanisms of inhibition than acting directly in the conserved ATP cleft
have been rarely explored or exploited in the kinase area [85, 86]. Only few kinases
exhibit a true allosteric site (e.g., ABL) which could have been targeted to design a
more specific generation of kinases inhibitors. In addition, to the best of our
knowledge, approaches which were based on protein-protein interactions inhibition
have failed to afford potent inhibitors except in the case of Akt [87]. Further
investigations in new assay developments for hit-finding based, for example, on
protein conformation changes [88] or in silico calculations to detect potential
additional binding sites [89], should open new avenues for selective and specific
kinase inhibitor discovery and development.
Compliance with Ethical Standards
Conflict of Interest: All authors are employees of Sanofi R&D and may hold stock in the same. All
authors declare no conflict of interest.
Funding: All studies were funded only by Sanofi R&D.
Ethical Approval: This chapter does not contain any studies with human participants or animals
performed by any of the authors.
Informed Consent: No human studies are reported; no informed consent required.
Achieving High Levels of Selectivity for Kinase Inhibitors
119
residue is Asn836, which is also located at $7 Å from the ligand and connected to
Water1 via a similar network (Fig. 20b). Due to a more efficient charge transfer
realized with Asp856 compared to the neutral Asn836, translated into more H-bonds
to Water1, and shortest distances within the water network, PI3Kβ better tolerates
the destabilizing influences of the methyl group in the (S)-configuration than PI3Kδ,
which encloses Water1 in a more hydrophobic environment, leading to the observed
selectivity. Interestingly, this hypothesis reconnects to the privileged residue analysis [23] as Asp856 is one of them.
Compound (S)-27 became eventually SAR301260, a clinical development candidate tested in PTEN-deficient cancer patients [84].
6 Conclusions
Through the aforementioned projects which have been described, it was possible to
identify and design very selective kinase inhibitors and dial out off-target affinity vs
close kinase neighbors. If state-of-the art technologies were applied during the
course of those projects (in biophysics, in modeling, etc.), serendipity in screens or
in chemistry remained a significant contributor to these successful drug discovery
programs. Moreover, exquisite selectivity was in certain circumstances rationalized
a posteriori rather than guided (e.g., PI3Kβ). Still, the key protein elements or ligand
properties which were identified to obtain and improve selectivity in one case or
another have served subsequent kinase projects in our group and knowledge
increased by experience for better efficiency. It is worth mentioning that other
types of mechanisms of inhibition than acting directly in the conserved ATP cleft
have been rarely explored or exploited in the kinase area [85, 86]. Only few kinases
exhibit a true allosteric site (e.g., ABL) which could have been targeted to design a
more specific generation of kinases inhibitors. In addition, to the best of our
knowledge, approaches which were based on protein-protein interactions inhibition
have failed to afford potent inhibitors except in the case of Akt [87]. Further
investigations in new assay developments for hit-finding based, for example, on
protein conformation changes [88] or in silico calculations to detect potential
additional binding sites [89], should open new avenues for selective and specific
kinase inhibitor discovery and development.
Compliance with Ethical Standards
Conflict of Interest: All authors are employees of Sanofi R&D and may hold stock in the same. All
authors declare no conflict of interest.
Funding: All studies were funded only by Sanofi R&D.
Ethical Approval: This chapter does not contain any studies with human participants or animals
performed by any of the authors.
Informed Consent: No human studies are reported; no informed consent required.
Achieving High Levels of Selectivity for Kinase Inhibitors
119