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PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

ABSTRACT: Proteolysis targeting chimeras (PROTACs) represent an emerging class of compounds for innovative therapeutic application. Their bifunctional nature induces the formation of a ternary complex (target protein/PROTAC/E3 ligase) which allows target protein ubiquitination and subsequent proteasomal-dependent degradation. To date, despite great efforts being made to improve their biological efficacy PROTACs rational design still represents a challenging task, above all for the modulation of their physicochemical and pharmacokinetics properties. Considering the pivotal role played by the linker moiety, recently the insertion of a piperazine moiety into the PROTAC linker has been widely used, as this ring can in principle improve rigidity and increase solubility upon protonation. Nevertheless, the pK _a of the piperazine ring is significantly affected by the chemical groups located nearby, and slight modifications in the linker could eliminate the desired effect. In the present study, the pK _a values of a dataset of synthesized small molecule compounds including PROTACs and their precursors have been evaluated in order to highlight how a fine modulation of piperazine-containing linkers can impact the protonation state of these molecules or similar heterobifunctional ones. Finally, the possibility of predicting the trend through in silico approaches was also evaluated.

SUBMITTER: Desantis J

PROVIDER: S-EPMC9361468 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

Desantis Jenny J Mammoli Andrea A Eleuteri Michela M Coletti Alice A Croci Federico F Macchiarulo Antonio A Goracci Laura L

RSC advances 20220809 34

Proteolysis targeting chimeras (PROTACs) represent an emerging class of compounds for innovative therapeutic application. Their bifunctional nature induces the formation of a ternary complex (target protein/PROTAC/E3 ligase) which allows target protein ubiquitination and subsequent proteasomal-dependent degradation. To date, despite great efforts being made to improve their biological efficacy PROTACs rational design still represents a challenging task, above all for the modulation of their phys ...[more]

PMID: 36043064

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PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

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PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

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