Open AccessThe molecular determinants of R-roscovitine block of hERG channels
Author(s) -
Bryan Cernuda,
Christopher Thomas Fernandes,
Salma Allam,
Matthew Orzillo,
Gabrielle Suppa,
Zuleen Chia Chang,
D. Athanasopoulos,
Zafir Buraei
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0217733
Subject(s) - herg , pharmacology , potassium channel , chemistry , cyclin dependent kinase , cardiac action potential , potassium channel blocker , repolarization , biology , biophysics , biochemistry , apoptosis , electrophysiology , medicine , cell cycle
H uman e ther-à-go-go- r elated g ene (Kv11.1, or hERG) is a potassium channel that conducts the delayed rectifier potassium current (I Kr ) during the repolarization phase of cardiac action potentials. hERG channels have a larger pore than other K + channels and can trap many unintended drugs, often resulting in acquired LQTS (aLQTS). R -roscovitine is a cyclin-dependent kinase (CDK) inhibitor that induces apoptosis in colorectal, breast, prostate, multiple myeloma, other cancer cell lines, and tumor xenografts, in micromolar concentrations. It is well tolerated in phase II clinical trials. R -roscovitine inhibits open hERG channels but does not become trapped in the pore. Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type (WT) or hERG pore mutant channels (T623A, S624A, Y652A, F656A) demonstrated that compared to WT hERG, T623A, Y652A, and F656A inhibition by 200 μM R -roscovitine was ~ 48%, 29%, and 73% weaker, respectively. In contrast, S624A hERG was inhibited more potently than WT hERG, with a ~ 34% stronger inhibition. These findings were further supported by the IC 50 values, which were increased for T623A, Y652A and F656A (by ~5.5, 2.75, and 42 fold respectively) and reduced 1.3 fold for the S624A mutant. Our data suggest that while T623, Y652, and F656 are critical for R -roscovitine-mediated inhibition, S624 may not be. Docking studies further support our findings. Thus, R- roscovitine’s relatively unique features, coupled with its tolerance in clinical trials, could guide future drug screens.