A5049458323- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Cell death mechanisms and regulation
- Multiple Myeloma Research and Treatments
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Histone Deacetylase Inhibitors Research
- ATP Synthase and ATPases Research
- RNA Interference and Gene Delivery
- Epigenetics and DNA Methylation
- Cytokine Signaling Pathways and Interactions
- Cancer therapeutics and mechanisms
- Cancer-related gene regulation
- interferon and immune responses
- Angiogenesis and VEGF in Cancer
- Chronic Lymphocytic Leukemia Research
- Glycosylation and Glycoproteins Research
- Cancer Research and Treatments
- Chronic Myeloid Leukemia Treatments
- RNA Research and Splicing
- Click Chemistry and Applications
- Signaling Pathways in Disease
- Genomics and Chromatin Dynamics
- Hedgehog Signaling Pathway Studies
- HIV Research and Treatment
University of Michigan
2015-2024
Hunan Academy of Agricultural Sciences
2024
Michigan Center for Translational Pathology
2014-2021
Shanghai Ocean University
2014
Michigan United
2013-2014
Chinese Academy of Fishery Sciences
2014
Palmetto Hematology Oncology
2005-2012
Emory University
2011
Icahn School of Medicine at Mount Sinai
2011
Shanghai Institute of Organic Chemistry
2008
The bromodomain and extra-terminal (BET) family proteins, consisting of BRD2, BRD3, BRD4, testis-specific BRDT members, are epigenetic "readers" play a key role in the regulation gene transcription. BET proteins considered to be attractive therapeutic targets for cancer other human diseases. Recently, heterobifunctional small-molecule degraders have been designed based upon proteolysis targeting chimera (PROTAC) concept induce protein degradation. Herein, we present our design, synthesis,...
Abstract Blocking the oncoprotein murine double minute 2 (MDM2)–p53 protein–protein interaction has long been considered to offer a broad cancer therapeutic strategy, despite potential risks of selecting tumors harboring p53 mutations that escape MDM2 control. In this study, we report novel small-molecule inhibitor MDM2–p53 interaction, SAR405838 (MI-77301), advanced into phase I clinical trials. binds with Ki = 0.88 nmol/L and high specificity over other proteins. A cocrystal structure...
Proteins of the bromodomain and extra-terminal (BET) family are epigenetics "readers" promising therapeutic targets for cancer other human diseases. We describe herein a structure-guided design [1,4]oxazepines as new class BET inhibitors our subsequent design, synthesis, evaluation proteolysis-targeting chimeric (PROTAC) small-molecule degraders. Our efforts have led to discovery extremely potent degraders, exemplified by QCA570, which effectively induces degradation proteins inhibits cell...
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development second-generation BET protein degrader, BETd-246, which exhibits superior selectivity, potency, and antitumor activity. human TNBC cells, BETd-246 induced degradation proteins at low nanomolar concentrations within 1 hour exposure, resulting in robust growth inhibition apoptosis. was more potent effective cells than its parental inhibitor...
Signal transducer and activator of transcription 3 (STAT3) is a factor an attractive therapeutic target for cancer other human diseases. Despite 20 years persistent research efforts, targeting STAT3 has been very challenging. We report herein the structure-based discovery potent small-molecule degraders based upon proteolysis chimera (PROTAC) concept. first designed SI-109 as potent, inhibitor SH2 domain. Employing ligands cereblon/cullin 4A E3 ligase SI-109, we obtained series PROTAC...
Small-molecule Smac mimetics are being developed as a novel class of anticancer drugs. Recent studies have shown that target cellular inhibitor apoptosis protein (cIAP)-1/2 for degradation and induce tumor necrosis factor-alpha (TNFalpha)-dependent in cells. In this study, we investigated the mechanism action therapeutic potential two different types mimetics, monovalent SM-122 bivalent SM-164. Our data showed removal cIAP-1/2 by or small interfering RNA is not sufficient robust...
Smac/DIABLO is a protein released from mitochondria into the cytosol in response to apoptotic stimuli. Smac promotes apoptosis at least part through antagonizing inhibitor of proteins (IAPs), including XIAP, cIAP-1, and cIAP-2. interacts with these IAPs via its N-terminal AVPI binding motif. There has been an enormous interest academic laboratories pharmaceutical companies design small-molecule mimetics as potential anticancer agents. This task particularly challenging because it involves...
Small-molecule inhibitors of bromodomain and extra terminal proteins (BET), including BRD2, BRD3, BRD4 have therapeutic potential for the treatment human cancers other diseases conditions. In this paper, we report design, synthesis, evaluation γ-carboline-containing compounds as a new class small-molecule BET inhibitors. The most potent inhibitor (compound 18, RX-37) obtained from study binds to (BRD2, BRD4) with Ki values 3.2-24.7 nM demonstrates high selectivity over non-BET...
We report herein the discovery and extensive characterization of ARD-1676, a highly potent orally efficacious PROTAC degrader androgen receptor (AR). ARD-1676 was designed using new class AR ligands novel cereblon ligand. It has DC50 values 0.1 1.1 nM in AR+ VCaP LNCaP cell lines, respectively, IC50 11.5 2.8 respectively. effectively induces degradation broad panel clinically relevant mutants. an oral bioavailability 67, 44, 31, 99% mice, rats, dogs, monkeys, Oral administration reduces...
CBP/p300 proteins are key epigenetic regulators and promising targets for the treatment of castration-resistant prostate cancer other types human cancers. Herein, we report discovery characterization CBPD-268 as an exceptionally potent, effective, orally efficacious PROTAC degrader proteins. induces degradation in three androgen receptor-positive cell lines, with DC50 ≤ 0.03 nM Dmax > 95%, leading to potent growth inhibition. It has excellent oral bioavailability mice rats. Oral...
CBP/p300 are critical transcriptional coactivators of the androgen receptor (AR) and promising cancer therapeutic targets. Herein, we report discovery highly potent, selective, orally bioavailable degraders using PROTAC technology with CBPD-409 being most compound. induces robust degradation DC50 0.2–0.4 nM displays strong antiproliferative effects IC50 1.2–2.0 in VCaP, LNCaP, 22Rv1 AR+ prostate cell lines. It has a favorable pharmacokinetic profile achieves 50% oral bioavailability mice. A...
We report herein the structure-based design of a class conformationally constrained, potent, cell-permeable small-molecule inhibitors to target SH2 domain in STAT3. Compound 11 (CJ-1383) binds STAT3 with K(i) value 0.95 µM, dose-dependently inhibits cellular signaling and cancer cell growth, induces apoptosis MDA-MB-468 line constitutively activated
Bcl-2 and Bcl-xL are critical regulators of apoptosis that overexpressed in a variety human cancers pharmacological inhibition represents promising strategy for cancer treatment. Using structure-based design approach, we have designed BM-1197 as potent efficacious dual inhibitor Bcl-xL. binds to proteins with Ki values less than 1 nM shows >1,000-fold selectivity over Mcl-1. Mechanistic studies performed the Mcl-1 knockout mouse embryonic fibroblast (MEF) cells revealed potently...
Development of B-cell lymphoma 2 (BCL-2)-specific inhibitors poses unique challenges in drug design because BCL-2 homology domain 3 (BH3) shared between family members and the shallow surface their protein-protein interactions. We report herein discovery extensive preclinical investigation lisaftoclax (APG-2575).Computational modeling was used to "lead" compounds. Biochemical binding, mitochondrial BH3 profiling, cell-based viability or apoptosis assays were determine selectivity potency...
Estrogen receptor α (ERα) is a prime target for the treatment of ER-positive (ER+) breast cancer. Despite development several effective therapies targeting ERα signaling, clinical resistance remains major challenge. In this study, we report discovery new class potent and orally bioavailable degraders using PROTAC technology, with ERD-3111 being most promising compound. exhibits in vitro degradation activity against demonstrates high oral bioavailability mice, rats, dogs. Oral administration...
STAT5 is an attractive therapeutic target for human cancers. We report herein the discovery of a potent and selective degrader with strong antitumor activity in vivo. first obtained small-molecule ligands sub-micromolar to low micromolar binding affinities STAT6 SH2 domains determined co-crystal structures three such complex STAT5A. successfully transformed these into degraders using PROTAC technology AK-2292 as best compound. effectively induces degradation STAT5A, STAT5B, phosphorylated...
Transcription factor p53 can induce growth arrest and/or apoptosis in cells through activation or repression of downstream target genes. Recently, we reported that ZBP-89 cooperates with histone acetyltransferase coactivator p300 the regulation p21(waf1), a cyclin-dependent kinase inhibitor whose associated gene is p53. Therefore, examined whether might also inhibit cell by activating In present study, demonstrate elevated levels and human gastrointestinal lines. The protein accumulated...
Helicobacter pylori evades host immune defenses and causes chronic gastritis. Immunity against intestinal pathogens is largely mediated by dendritic cells, yet the role of cells in acute H. infection unknown. We observed recruitment to gastric mucosa pylori-infected mice. Bone marrow-derived from mice responded live upregulating expression proinflammatory cytokine mRNA (i.e., IL-1α, IL-1β, IL-6). The supernatant stimulated with for 18 h contained twofold higher levels IL-12p70 than IL-10...