2 research outputs found
Tunable Growth Factor Delivery from Injectable Hydrogels for Tissue Engineering
Current sustained delivery strategies of protein therapeutics
are
limited by the fragility of the protein, resulting in minimal quantities
of bioactive protein delivered. In order to achieve prolonged release
of bioactive protein, an affinity-based approach was designed which
exploits the specific binding of the Src homology 3 (SH3) domain with
short proline-rich peptides. Specifically, methyl cellulose was modified
with SH3-binding peptides (MC-peptide) with either a weak affinity
or strong affinity for SH3. The release profile of SH3-rhFGF2 fusion
protein from hyaluronan MC-SH3 peptide (HAMC-peptide) hydrogels was
investigated and compared to unmodified controls. SH3-rhFGF2 release
from HAMC-peptide was extended to 10 days using peptides with different
binding affinities compared to the 48 h release from unmodified HAMC.
This system is capable of delivering additional proteins with tunable
rates of release, while maintaining bioactivity, and thus is broadly
applicable
Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/SMARCA2 ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/SMARCA4-Mutant Cancers
SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases