Exploration of drug design approaches with application to PIM-1 kinase and protein kinase A
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Abstract
In the context of this thesis, four distinct approaches for the design of novel inhibitors
targeting PIM-1 kinase and protein kinase A (PKA) were implemented and evaluated.
Design strategies were developed and selected molecules were synthesized, some following
structural modification. Each approach was supported by docking and the
analysis of binding modes derived from protein crystal structures or docking solutions.
The objective of this work was the evaluation of different drug design strategies
and the implementation of novel approaches for generating new kinase inhibitors of
PIM-1 kinase and PKA.
The first project involved the derivatization of an established scaffold for potential
PIM-1 kinase inhibitors within a hit-to-lead optimization. To improve synthetic accessibility
and facilitate structure elucidation, a quinoxaline scaffold was converted
into a benzimidazole-2-carboxylic acid core. The determination of a protein crystal
structure of this new fragment 20 enabled a fragment-based drug design approach,
in which various growing strategies were performed via docking to explore the PIM-
1 kinase binding pocket. During this process, a pronounced instability of the free
carboxylic acid was identified, preventing the successful synthesis of the planned
target structures. However, the decarboxylation of several derivatives led to compounds
exhibiting significant biological activity. Compound 91 emerged as the most
active derivative, showing a residual PIM-1 kinase activity of 18% at an inhibitor
concentration of 100 μM, thereby surpassing the biological activity of the original
quinoxaline-based hit.
The second project utilized a trans-stilbene hit against PIM-1 kinase as a starting point.
Due to synthetic and analytical restrictions of this scaffold, it was transitioned into
a structurally comparable 2-phenylbenzimidazole. This core was more synthetically
accessible and bypassed the limitations of cis/trans isomerism through conformational
fixation. A binding mode comparable to the stilbene hit was postulated based on docking
experiments using the available protein crystal structure. On this basis, a small
substance library was designed, synthesized, and biologically evaluated. However,
none of the synthesized derivatives reached the potency of the starting compound,
illustrating the limited transferability of structural hypotheses derived from docking
studies.
The third project implemented a combined strategy of ligand- and structure-based
drug design. The topology of highly active, literature-known PIM-1 kinase inhibitors
served as a template for scaffold hopping using FTrees. Within this framework, a
workflow was developed to identify structurally related compounds from chemical
spaces. A selection of these was visually evaluated regarding their synthetic accessibility
and predicted binding modes in PIM-1 kinase. The six selected structures were
successfully synthesized and investigated. Target compound 142 was identified as the
most promising lead (45% residual activity at an inhibitor concentration of 100 μM)
due to its fragment-like size. Based on 142, a SAR analysis established compound 147
as a more active bioisostere (25% residual activity). In a second design cycle, 147 was
to be further optimized. The replacement of a benzene ring with a thiophene was
intended to enable an interaction predicted by docking, which could not be confirmed
in a protein crystal structure of PIM-1 kinase in complex with 147. Furthermore, a
growing approach was aimed at establishing additional interactions. In both cases, the
target structures could not be successfully synthesized due to unanticipated synthetic
restrictions.
The fourth project involved the implementation of a data-driven approach within
a case study for the design of novel PKA inhibitors, developed in cooperation with
the Volkamer group (Saarland University). The approach utilized subpocket-based
docking to combine promising fragments of kinase binders into novel, highly active
compounds. This led to the successful preparation of 15 compounds, synthesized in
cooperation with Naemi Wagner (AK Diederich, Marburg University). Seven of these
15 compounds reduced PKA activity to below 50% at an inhibitor concentration of
100 μM, with compound 208 (6% residual activity) and compound 211 (8% residual
activity) being the most active. The biological activity of 208 was further investigated,
showing that it reduces PKA activity to 14% even at an inhibitor concentration of
10 μM. Consequently, several highly active PKA inhibitors were identified through
this novel approach.
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Issued: 2026-04-20
Faculty
FB16:Pharmazie
Language
en
Keywords
kinasekinase inhibitorcomputer-aided drug design
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Hubach, Dominik: Exploration of drug design approaches with application to PIM-1 kinase and protein kinase A. : 2026-04-20. DOI: https://doi.org/10.17192/openumr/684.
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This item has been published with the following license: In Copyright