3 research outputs found
Optimization of a Kilogram-Scale Synthesis of a Potent Cycloartenol Triterpenoid-Derived γ‑Secretase Modulator
This work describes
the demonstration of a kilogram-scale synthesis
of a γ-secretase modulator from a plant-sterol-derived starting
material. Key to developing a synthetic route capable of delivering
a kilogram of the target compound was the development of a four-reaction
telescope process and a selective O-alkylation of a triol intermediate.
These improvements enabled the successful delivery of kilogram-scale
batches of API for preclinical development studies
Initial Optimization of a New Series of γ‑Secretase Modulators Derived from a Triterpene Glycoside
The discovery of a new series of γ-secretase modulators
is
disclosed. Starting from a triterpene glycoside γ-secretase
modulator that gave a very low brain-to-plasma ratio, initial SAR
and optimization involved replacement of a pendant sugar with a series
of morpholines. This modification led to two compounds with significantly
improved central nervous system (CNS) exposure
Discovery of Pyrazolo[1,5‑<i>a</i>]pyrimidine B‑Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors
Inhibition of the protein–protein
interaction between B-cell
lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic
target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling
of potent and selective BCL6 inhibitors are critical to test this
hypothesis. We identified a pyrazoloÂ[1,5-<i>a</i>]Âpyrimidine
series of BCL6 binders from a fragment screen in parallel with a virtual
screen. Using structure-based drug design, binding affinity was increased
100000-fold. This involved displacing crystallographic water, forming
new ligand–protein interactions and a macrocyclization to favor
the bioactive conformation of the ligands. Optimization for slow off-rate
constant kinetics was conducted as well as improving selectivity against
an off-target kinase, CK2. Potency in a cellular BCL6 assay was further
optimized to afford highly selective probe molecules. Only weak antiproliferative
effects were observed across a number of DLBCL lines and a multiple
myeloma cell line without a clear relationship to BCL6 potency. As
a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains
unproven