16 research outputs found
Unveiling the State Transition Mechanisms of Ras Proteins through Enhanced Sampling and QM/MM Simulations
In
cells, wild-type RasGTP complexes exist in two distinct
states:
active State 2 and inactive State 1. These complexes regulate their
functions by transitioning between the two states. However, the mechanisms
underlying this state transition have not been clearly elucidated.
To address this, we conducted a detailed simulation study to characterize
the energetics of the stable states involved in the state transitions
of the HRasGTP complex, specifically from State 2 to State 1. This
was achieved by employing multiscale quantum mechanics/molecular mechanics
and enhanced sampling molecular dynamics methods. Based on the simulation
results, we constructed the two-dimensional free energy landscapes
that provide crucial information about the conformational changes
of the HRasGTP complex from State 2 to State 1. Furthermore, we also
explored the conformational changes from the intermediate state to
the product state during guanosine triphosphate hydrolysis. This study
on the conformational changes involved in the HRas state transitions
serves as a valuable reference for understanding the corresponding
events of both KRas and NRas as well
Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a Potent and Selective Inhibitor of Big MAP Kinase 1
Kinome-wide selectivity profiling of a collection of 2-amino-pyrido[2,3-d]pyrimidines followed by cellular structure−activity relationship-guided optimization resulted in the identification of moderately potent and selective inhibitors of BMK1/ERK5 exemplified by <b>11</b>, <b>18</b>, and <b>21</b>. For example, <b>11</b> possesses a dissociation constant (<i>K</i><sub>d</sub>) for BMK1 of 19 nM, a cellular IC<sub>50</sub> for inhibiting epidermal growth factor induced BMK1 autophosphorylation of 0.19 ± 0.04 μM, and an Ambit KINOME<i>scan</i> selectivity score (<i>S</i><sub>5</sub>) of 0.035. Inhibitors <b>18</b> and <b>21</b> are also potent BMK1 inhibitors and possess favorable pharmacokinetic properties which enable their use as pharmacological probes of BMK1-dependent phenomena as well as starting points for further optimization efforts
Discovery of a benzo[e]pyrimido-[5,4-b][1,4]diazepin-6(11H)-one as a Potent and Selective Inhibitor of Big MAP Kinase 1
Kinome-wide selectivity profiling of a collection of 2-amino-pyrido[2,3-d]pyrimidines followed by cellular structure−activity relationship-guided optimization resulted in the identification of moderately potent and selective inhibitors of BMK1/ERK5 exemplified by <b>11</b>, <b>18</b>, and <b>21</b>. For example, <b>11</b> possesses a dissociation constant (<i>K</i><sub>d</sub>) for BMK1 of 19 nM, a cellular IC<sub>50</sub> for inhibiting epidermal growth factor induced BMK1 autophosphorylation of 0.19 ± 0.04 μM, and an Ambit KINOME<i>scan</i> selectivity score (<i>S</i><sub>5</sub>) of 0.035. Inhibitors <b>18</b> and <b>21</b> are also potent BMK1 inhibitors and possess favorable pharmacokinetic properties which enable their use as pharmacological probes of BMK1-dependent phenomena as well as starting points for further optimization efforts
Structure Determinants of Lagunamide A for Anticancer Activity and Its Molecular Mechanism of Mitochondrial Apoptosis
Marine
natural products are served as attractive source of anticancer
therapeutics, with the great success of “first-in-class”
drugs, such as Yondelis, Halaven, and Brentuximab vendotin. Lagunamides
A–C from marine cyanobacterium, <i>Lyngbya majuscula</i>, exhibit exquisite growth inhibitory activities against cancer cells.
In this study, we have systematically investigated the structure–activity
relationships (SARs) of a concise collection of lagunamide A and its
analogues constructed by total chemical synthesis against a broad
panel of cancer cells derived from various tissues or organs, including
A549, HeLa, U2OS, HepG2, BEL-7404, BGC-823, HCT116, MCF-7, HL-60,
and A375. The <i>R</i> configuration of lagunamide A at
C-39 position was found to be the structure determinant for anticancer
activity. Further molecular mechanism study in A549 cells revealed
that lagunamide A induced caspase-mediated mitochondrial apoptosis.
Accompanied with the dissipation of mitochondrial membrane potential
(Δφm) and overproduction of reactive oxygen species (ROS),
lagunamide A led to mitochondrial dysfunction and finally caused cell
death. Moreover, both anti- and pro-apoptotic B-cell lymphoma 2 (Bcl-2)
family proteins participated in lagunamide A-induced mitochondrial
apoptosis, especially myeloid cell leukemia-1 (Mcl-1). Overexpression
of Mcl-1 partly rescued A549 cells from lagunamide A-induced apoptosis.
This study suggests that lagunamide A may exert anticancer property
through mitochondrial apoptosis. Together, our findings would provide
insightful information for the design of new anticancer drugs derived
from lagunamides
Brain Penetrant LRRK2 Inhibitor
Activating mutations in leucine-rich repeat kinase 2
(LRRK2) are
present in a subset of Parkinson's disease (PD) patients and may represent
an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5-chloropyrimidine,
HG-10-102-01 (<b>4</b>), is a potent and selective inhibitor
of wild-type LRRK2 and the G2019S mutant. Compound <b>4</b> substantially
inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2
and G2019S mutant at a concentration of 0.1–0.3 μM in
cells and is the first compound reported to be capable of inhibiting
Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal
delivery of doses as low as 50 mg/kg
Selective Aurora Kinase Inhibitors Identified Using a Taxol-Induced Checkpoint Sensitivity Screen
The members of the Aurora kinase family play critical
roles in
the regulation of the cell cycle and mitotic spindle assembly and
have been intensively investigated as potential targets for a new
class of anticancer drugs. We describe a new highly potent and selective
class of Aurora kinase inhibitors discovered using a phenotypic cellular
screen. Optimized inhibitors display many of the hallmarks of Aurora
inhibition including endoreduplication, polyploidy, and loss of cell
viability in cancer cells. Structure–activity relationships
with respect to kinome-wide selectivity and guided by an Aurora B
co-crystal structure resulted in the identification of key selectivity
determinants and discovery of a subseries with selectivity toward
Aurora A. A direct comparison of biochemical and cellular profiles
with respect to published Aurora inhibitors including VX-680, AZD1152,
MLN8054, and a pyrimidine-based compound from Genentech demonstrates
that compounds <b>1</b> and <b>3</b> will become valuable
additional pharmacological probes of Aurora-dependent functions
Discovery of 3,5-Diamino-1,2,4-triazole Ureas as Potent Anaplastic Lymphoma Kinase Inhibitors
A series of novel 3,5-diamino-1,2,4-triazole benzyl ureas was identified as having potent anaplastic lymphoma kinase (ALK) inhibition exemplified by <b>15a</b>, <b>20a</b>, and <b>23a</b>, which exhibited antiproliferative IC<sub>50</sub> values of 70, 40, and 20 nM in Tel-ALK transformed Ba/F3 cells, respectively. Moreover, <b>15a</b> and <b>23a</b> potently inhibited the growth and survival of NPM-ALK positive anaplastic large cell lymphoma cell (SU-DHL-1) and neuroblastoma cell lines (KELLY, SH-SY5Y) containing the F1174L ALK mutation. These compounds provide novel leads for the development of small-molecule ALK inhibitors for cancer therapy
Discovery and Identification of Small Molecules as Methuosis Inducers with <i>in Vivo</i> Antitumor Activities
Methuosis is a novel nonapoptotic
mode of cell death characterized
by vacuole accumulation in the cytoplasm. In this article, we describe
a series of azaindole-based compounds that cause vacuolization in
MDA-MB-231 cells. The most potent vacuole inducer, compound <b>13</b> (compound <b>13</b>), displayed differential cytotoxicities
against a broad panel of cancer cell lines, such as MDA-MB-231, A375,
HCT116, and MCF-7, but it did not inhibit the growth of the nontumorigenic
epithelial cell line MCF-10A. A mechanism study confirmed that the
cell death was caused by inducing methuosis. Furthermore, compound <b>13</b> exhibited substantial pharmacological efficacy in the suppression
of tumor growth in a xenograft mouse model of MDA-MB-231 cells without
apparent side effects, which makes this compound the first example
of a methuosis inducer with potent <i>in vivo</i> efficacy.
These results demonstrate that methuosis inducers might serve as novel
therapeutics for the treatment of cancer
Discovery of a Series of 5,11-Dihydro‑6<i>H</i>‑benzo[<i>e</i>]pyrimido[5,4‑<i>b</i>][1,4]diazepin-6-ones as Selective PI3K-δ/γ Inhibitors
Dual
inhibition of PI3K-δ and PI3K-γ is an established therapeutic
strategy for treatment of hematological malignancies. Reported molecules
targeting PI3K-δ/γ selectively are chemically similar
and based upon isoquinolin-1(2<i>H</i>)-one or quinazolin-4(3<i>H</i>)-one scaffolds. Here we report a chemically distinct series
of potent, selective PI3K-δ/γ inhibitors based on a 5,11-dihydro-6<i>H</i>-benzo[<i>e</i>]pyrimido[5,4-<i>b</i>][1,4]diazepin-6-one scaffold with comparable biochemical potency
and cellular effects on PI3K signaling. We envisage these molecules
will provide useful leads for development of next-generation PI3K-δ/γ
targeting therapeutics
Inhibition of RET/C634R and RET/M918T phosphorylation and downstream signaling by ALW-II-41-27, XMD15-44 and HG-6-63-01.
<p>A) Schematic representation of RET/C634R and RET/M918T proteins. EC: extracellular domain; IC: intracellular domain; TM: transmembrane domain. B-D) Serum-starved RAT1 RET/C634R and RAT1 RET/M918T or parental RAT1 cells were treated for 2 hr with the indicated concentrations of ALW-II-41-27, XMD15-44 and HG-6-63-01. 50 μg of total cell lysates were subjected to immunoblotting with phospho-Y1062 (αp1062), phospho-Y905 (αp905) RET antibodies, phospho-MAPK (αpMAPK) or phospho-SHC (αpSHC) antibodies. The blots were normalized using anti-RET (αRET), anti-MAPK (αMAPK) and anti-SHC (αSHC) antibodies.</p