9 research outputs found
Ivacaftor potentiation of multiple CFTR channels with gating mutations
AbstractBackgroundThe investigational CFTR potentiator ivacaftor (VX-770) increased CFTR channel activity and improved lung function in subjects with CF who have the G551D CFTR gating mutation. The aim of this in vitro study was to determine whether ivacaftor potentiates mutant CFTR with gating defects caused by other CFTR gating mutations.MethodsThe effects of ivacaftor on CFTR channel open probability and chloride transport were tested in electrophysiological studies using Fischer rat thyroid (FRT) cells expressing different CFTR gating mutations.ResultsIvacaftor potentiated multiple mutant CFTR forms with defects in CFTR channel gating. These included the G551D, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P and G1349D CFTR gating mutations.ConclusionThese in vitro data suggest that ivacaftor has a similar effect on all CFTR forms with gating defects and support investigation of the potential clinical benefit of ivacaftor in CF patients who have CFTR gating mutations beyond G551D
Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors
Mcl-1 is a pro-apoptotic
BH3 protein family member similar to Bcl-2
and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors
and allows cancer cells to evade apoptosis. Here we report the discovery
and optimization of a series of non-natural peptide Mcl-1 inhibitors.
Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure
demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn
conformation, such that the two ends of the peptide were close together.
This proximity allowed for the linking of the two ends of the peptide
to form a macrocycle. Macrocyclization resulted in an approximately
10-fold improvement in binding potency. Further exploration of a key
hydrophobic interaction with Mcl-1 protein and also with the moiety
that engages Arg256 led to additional potency improvements. The use
of protein–ligand crystal structures and binding kinetics contributed
to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at
only 5 μM and Bcl-xL at >99 μM, and induces cleaved
caspase-3
in MV4–11 cells with an IC<sub>50</sub> of 3 μM after
6 h
Structure Based Design of Non-Natural Peptidic Macrocyclic Mcl‑1 Inhibitors
Mcl-1 is a pro-apoptotic
BH3 protein family member similar to Bcl-2
and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors
and allows cancer cells to evade apoptosis. Here we report the discovery
and optimization of a series of non-natural peptide Mcl-1 inhibitors.
Screening of DNA-encoded libraries resulted in hit compound <b>1</b>, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure
demonstrated that compound <b>1</b> bound to Mcl-1 in a β-turn
conformation, such that the two ends of the peptide were close together.
This proximity allowed for the linking of the two ends of the peptide
to form a macrocycle. Macrocyclization resulted in an approximately
10-fold improvement in binding potency. Further exploration of a key
hydrophobic interaction with Mcl-1 protein and also with the moiety
that engages Arg256 led to additional potency improvements. The use
of protein–ligand crystal structures and binding kinetics contributed
to the design and understanding of the potency gains. Optimized compound <b>26</b> is a <3 nM Mcl-1 inhibitor, while inhibiting Bcl-2 at
only 5 μM and Bcl-xL at >99 μM, and induces cleaved
caspase-3
in MV4–11 cells with an IC<sub>50</sub> of 3 μM after
6 h