3 research outputs found
Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry
Recent
advances in understanding the relevance of noncoding RNA
(ncRNA) to disease have increased interest in drugging ncRNA with
small molecules. The recent discovery of ribocil, a structurally distinct
synthetic mimic of the natural ligand of the flavin mononucleotide
(FMN) riboswitch, has revealed the potential chemical diversity of
small molecules that target ncRNA. Affinity-selection mass spectrometry
(AS-MS) is theoretically applicable to high-throughput screening (HTS)
of small molecules binding to ncRNA. Here, we report the first application
of the Automated Ligand Detection System (ALIS), an indirect AS-MS
technique, for the selective detection of small molecule–ncRNA
interactions, high-throughput screening against large unbiased small-molecule
libraries, and identification and characterization of novel compounds
(structurally distinct from both FMN and ribocil) that target the
FMN riboswitch. Crystal structures reveal that different compounds
induce various conformations of the FMN riboswitch, leading to different
activity profiles. Our findings validate the ALIS platform for HTS
screening for RNA-binding small molecules and further demonstrate
that ncRNA can be broadly targeted by chemically diverse yet selective
small molecules as therapeutics
Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors
A new subseries of substituted piperidines
as p53-HDM2 inhibitors
exemplified by <b>21</b> has been developed from the initial
lead <b>1</b>. Research focused on optimization of a crucial
HDM2 Trp23–ligand interaction led to the identification of
2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation
of the Leu26 pocket resulted in potent, novel substituted piperidine
inhibitors of the HDM2-p53 interaction that demonstrated tumor regression
in several human cancer xenograft models in mice. The structure of
HDM2 in complex with inhibitors <b>3</b>, <b>10</b>, and <b>21</b> is described
Structure-Based Design of an Iminoheterocyclic β‑Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates
We
describe successful efforts to optimize the in vivo profile and address
off-target liabilities of a series of BACE1 inhibitors represented
by <b>6</b> that embodies the recently validated fused pyrrolidine
iminopyrimidinone scaffold. Employing structure-based design, truncation
of the cyanophenyl group of <b>6</b> that binds in the S3 pocket
of BACE1 followed by modification of the thienyl group in S1 was pursued.
Optimization of the pyrimidine substituent that binds in the S2′–S2″
pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier
analogues in this series and imparted high BACE1 affinity. These efforts
resulted in the discovery of difluorophenyl analogue <b>9</b> (MBi-4), which robustly lowered CSF and cortex Aβ<sub>40</sub> in both rats and cynomolgus monkeys following a single oral dose.
Compound <b>9</b> represents a unique molecular shape among
BACE inhibitors reported to potently lower central Aβ in nonrodent
preclinical species