Merrifield resin is converted to a solid-supported free radical initiator by reacting with the TEMPO-Na. Heating TEMPO-methyl resin with a variety of functionalized styrene and acrylate monomers gives larger resin beads via living free radical polymerization. We have coined the term Rasta resin to describe resin beads prepared in this fashion. The process can be described as a solvent-free suspension polymerization. It is particularly well suited for preparation of resin beads from monomers which contain electrophilic groups that would be destroyed upon suspension polymerization in water. Rasta resins have a novel macromolecular architecture wherein long straight chain polymers bearing reactive functional groups emanate from the phenyl groups of a cross-linked polystyrene core. With judicious choice of co-monomers and polymerization strategy, the solvent affinity, loading capacity, and distance of functionality from the cross-linked core may be controlled giving beads with properties that are tailored to specific uses as synthesis supports and scavenging resins.
Inhibition of the bromodomain and
extra-terminal (BET) family of
adaptor proteins is an attractive strategy for targeting transcriptional
regulation of key oncogenes, such as c-MYC. Starting with the screening
hit 1, a combination of structure–activity relationship
and protein structure-guided drug design led to the discovery of a
differently oriented carbazole 9 with favorable binding
to the tryptophan, proline, and phenylalanine (WPF) shelf conserved
in the BET family. Identification of an additional lipophilic pocket
and functional group optimization to optimize pharmacokinetic (PK)
properties culminated in the discovery of 18 (BMS-986158)
with excellent potency in binding and functional assays. On the basis
of its favorable PK profile and robust in vivo activity in a panel
of hematologic and solid tumor models, BMS-986158 was selected as
a candidate for clinical evaluation.
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