9 research outputs found
Electrophilic Helical Peptides That Bond Covalently, Irreversibly, and Selectively in a Protein–Protein Interaction Site
Protein–protein interactions
mediate most physiological and disease processes. Helix-constrained
peptides potently mimic or inhibit these interactions by making multiple
contacts over large surface areas. However, despite high affinities,
they typically have short lifetimes bound to the protein. Here we
insert both a helix-inducing constraint and an adjacent electrophile
into the native peptide ligand BIM to target the oncogenic protein
Bcl2A1. The modified BIM peptide bonds covalently and irreversibly
to one cysteine within the helix-binding groove of Bcl2A1, but not
to two other exposed cysteines on its surface, and shows no covalent
bonding to other Bcl2 proteins. It also penetrates cell membranes
and bonds covalently to Bcl2A1 inside cells. This innovative approach
to increasing receptor residence time of helical peptides demonstrates
the potential to selectively silence a PPI inside cells, with selectivity
over other nucleophilic sites on proteins
气候统计分析方法及其应用-1
A 26-residue peptide
BimBH3 binds indiscriminately to multiple
oncogenic Bcl2 proteins that regulate apoptosis of cancer cells. Specific
inhibition of the BimBH3-Bcl2A1 protein–protein interaction
was obtained <i>in vitro</i> and in cancer cells by shortening
the peptide to 14 residues, inserting two cyclization constraints
to stabilize a water-stable α-helix, and incorporating an N-terminal
acrylamide electrophile for selective covalent bonding to Bcl2A1.
Mass spectrometry of trypsin-digested bands on electrophoresis gels
established covalent bonding of an electrophilic helix to just one
of the three cysteines in Bcl2A1, the one (Cys55) at the BimBH3-Bcl2A1
protein–protein interaction interface. Optimizing the helix-inducing
constraints and the sequence subsequently enabled electrophile removal
without loss of inhibitor potency. The bicyclic helical peptides were
potent, cell permeable, plasma-stable, dual inhibitors of Bcl2A1 and
Mcl-1 with high selectivity over other Bcl2 proteins. One bicyclic
peptide was shown to inhibit the interaction between a pro-apoptotic
protein (Bim) and either endogenous Bcl2A1 or Mcl-1, to induce apoptosis
of SKMel28 human melanoma cells, and to sensitize them for enhanced
cell death by the anticancer drug etoposide. These approaches look
promising for chemically silencing intracellular proteins
Molecular Shape and Medicinal Chemistry: A Perspective
Molecular Shape and Medicinal Chemistry: A Perspectiv
Implications of Promiscuous Pim-1 Kinase Fragment Inhibitor Hydrophobic Interactions for Fragment-Based Drug Design
We have studied the subtleties of fragment docking and
binding
using data generated in a Pim-1 kinase inhibitor program. Crystallographic
and docking data analyses have been undertaken using inhibitor complexes
derived from an in-house surface plasmon resonance (SPR) fragment
screen, a virtual needle screen, and a de novo designed fragment inhibitor
hybrid. These investigations highlight that fragments that do not
fill their binding pocket can exhibit promiscuous hydrophobic interactions
due to the lack of steric constraints imposed on them by the boundaries
of said pocket. As a result, docking modes that disagree with an observed
crystal structure but maintain key crystallographically observed hydrogen
bonds still have potential value in ligand design and optimization.
This observation runs counter to the lore in fragment-based drug design
that all fragment elaboration must be based on the parent crystal
structure alone
Acyl Guanidine Inhibitors of β‑Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis
This report describes the discovery and optimization
of a BACE-1
inhibitor series containing an unusual acyl guanidine chemotype that
was originally synthesized as part of a 6041-membered solid-phase
library. The synthesis of multiple follow-up solid- and solution-phase
libraries facilitated the optimization of the original micromolar
hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand
binding and cell-based functional assay formats. The X-ray structure
of representative inhibitors bound to BACE-1 revealed a number of
key ligand:protein interactions, including a hydrogen bond between
the side chain amide of flap residue Gln73 and the acyl guanidine
carbonyl group, and a cation−π interaction between Arg235
and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous
administration in rats, an acyl guanidine inhibitor with single-digit
nanomolar activity in cells afforded good plasma exposures and a dose-dependent
reduction in plasma Aβ levels, but poor brain exposure was observed
(likely due to Pgp-mediated efflux), and significant reductions in
brain Aβ levels were not obtained
Identification of (<i>R</i>)‑<i>N</i>‑((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)‑1<i>H</i>‑indole-3-carboxamide (CPI-1205), a Potent and Selective Inhibitor of Histone Methyltransferase EZH2, Suitable for Phase I Clinical Trials for B‑Cell Lymphomas
Polycomb
repressive complex 2 (PRC2) has been shown to play a major
role in transcriptional silencing in part by installing methylation
marks on lysine 27 of histone 3. Dysregulation of PRC2 function correlates
with certain malignancies and poor prognosis. EZH2 is the catalytic
engine of the PRC2 complex and thus represents a key candidate oncology
target for pharmacological intervention. Here we report the optimization
of our indole-based EZH2 inhibitor series that led to the identification
of CPI-1205, a highly potent (biochemical IC<sub>50</sub> = 0.002
μM, cellular EC<sub>50</sub> = 0.032 μM) and selective
inhibitor of EZH2. This compound demonstrates robust antitumor effects
in a Karpas-422 xenograft model when dosed at 160 mg/kg BID and is
currently in Phase I clinical trials. Additionally, we disclose the
co-crystal structure of our inhibitor series bound to the human PRC2
complex
Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor
The
design and synthesis of potent, tripeptidic acylsulfonamide
inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl
amino acid at P1 are described. A cocrystal structure of <b>18</b> with a NS3/4A protease complex suggests the presence of a H-bond
between the polarized C–H of the CHF<sub>2</sub> moiety and
the backbone carbonyl of Leu135 of the enzyme. Structure–activity
relationship studies indicate that this H-bond enhances enzyme inhibitory
potency by 13- and 17-fold compared to the CH<sub>3</sub> and CF<sub>3</sub> analogues, respectively, providing insight into the deployment
of this unique amino acid
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains
The
biological role played by non-BET bromodomains remains poorly understood,
and it is therefore imperative to identify potent and highly selective
inhibitors to effectively explore the biology of individual bromodomain
proteins. A ligand-efficient nonselective bromodomain inhibitor was
identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic
substituents replacing the <i>N</i>-methyl group were designed
directing toward the conserved bromodomain water pocket, and two distinct
binding conformations were then observed. The substituents either
directly displaced and rearranged the conserved solvent network, as
in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent
to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct
substituents for individual bromodomains provided selectivity handles
useful for future lead optimization efforts for selective BRD9, CECR2,
and TAF1(2) inhibitors
Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection
The discovery of BMS-605339 (<b>35</b>), a tripeptidic inhibitor of the NS3/4A enzyme, is described.
This compound incorporates a cyclopropylacylsulfonamide moiety
that was designed to improve the potency of carboxylic acid prototypes
through the introduction of favorable nonbonding interactions within
the S1′ site of the protease. The identification of <b>35</b> was enabled through the optimization and balance of critical properties
including potency and pharmacokinetics (PK). This was achieved through
modulation of the P2* subsite of the inhibitor which identified the
isoquinoline ring system as a key template for improving PK properties
with further optimization achieved through functionalization. A methoxy
moiety at the C6 position of this isoquinoline ring system proved
to be optimal with respect to potency and PK, thus providing the clinical
compound <b>35</b> which demonstrated antiviral activity in
HCV-infected patients