A5085723739- Chronic Lymphocytic Leukemia Research
- Chronic Myeloid Leukemia Treatments
- Cancer-related Molecular Pathways
- Cell death mechanisms and regulation
- Acute Lymphoblastic Leukemia research
- Ubiquitin and proteasome pathways
- Cancer Mechanisms and Therapy
- Acute Myeloid Leukemia Research
- Chemical Synthesis and Analysis
- Multiple Myeloma Research and Treatments
- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Protein Kinase Regulation and GTPase Signaling
- Lymphoma Diagnosis and Treatment
- Lung Cancer Treatments and Mutations
- PI3K/AKT/mTOR signaling in cancer
- RNA Interference and Gene Delivery
- Cancer Research and Treatments
- Gastric Cancer Management and Outcomes
- Peptidase Inhibition and Analysis
- Advanced Breast Cancer Therapies
- Protein Degradation and Inhibitors
- Click Chemistry and Applications
- Cancer therapeutics and mechanisms
- Lung Cancer Research Studies
Sun Yat-sen University
2016-2025
Sun Yat-sen University Cancer Center
2016-2025
North Sichuan Medical University
2024-2025
State Key Laboratory of Oncology in South China
2015-2024
Vifor Pharma (United States)
2024
Fudan University
2023
Zhongshan Hospital of Xiamen University
2023
Zhongshan Hospital
2023
Flow Pharma (United States)
2023
The First Affiliated Hospital, Sun Yat-sen University
2023
We have designed MI-219 as a potent, highly selective and orally active small-molecule inhibitor of the MDM2–p53 interaction. binds to human MDM2 with K i value 5 nM is 10,000-fold for over MDMX. It disrupts interaction activates p53 pathway in cells wild-type p53, which leads induction cell cycle arrest all apoptosis tumor cells. stimulates rapid but transient activation established xenograft tissues, resulting inhibition proliferation, apoptosis, complete growth inhibition. normal tissues...
We report the discovery and characterization of SM-406 (compound 2), a potent orally bioavailable Smac mimetic an antagonist inhibitor apoptosis proteins (IAPs). This compound binds to XIAP, cIAP1, cIAP2 with Ki 66.4, 1.9, 5.1 nM, respectively. Compound 2 effectively antagonizes XIAP BIR3 protein in cell-free functional assay, induces rapid degradation cellular cIAP1 protein, inhibits cancer cell growth various human lines. It has good oral bioavailability mice, rats, non-human primates,...
// Miaozhen Qiu 1,2,* , Jianming Hu 3,* Dajun Yang 4,* David Peter Cosgrove 2 and Ruihua Xu 1 Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory Oncology in South China, Collaborative Innovation Center for Medicine, Guangzhou, China The Sidney Kimmel Comprehensive Johns Hopkins School Baltimore, MD, USA 3 Imaging Department, 4 Experimental Research, * These authors have contributed equally to this work Correspondence to: Xu, email: Keywords :...
We previously reported the design of spirooxindoles with two identical substituents at carbon-2 pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure–activity relationship study class inhibitors, which led to discovery 60 (AA-115/APG-115). Compound has a very high affinity (Ki < 1 nM), cellular activity, and excellent oral pharmacokinetic profile. is capable achieving complete long-lasting tumor regression in vivo currently phase I clinical trials for...
Bcl-2 family members play an important role in the development of malignant lymphoma and can induce drug resistance anticancer treatment. The small molecules targeting proteins may be a new strategy for treatment lymphoma. In this study, we investigate antitumor effect cellular mechanism novel Bcl-2/Bcl-xL dual inhibitor, BM-1197, DCBCL Burkitt cells.The CCK-8 assay was used to detect cell viability. Apoptosis determined by Hoechst 33258 staining flow cytometry. activity caspase-3/caspase-9...
The X-linked inhibitor of apoptosis (XIAP) is a promising new molecular target for the design novel anticancer drugs aiming at overcoming apoptosis-resistance cancer cells to chemotherapeutic agents and radiation therapy. Recent studies demonstrated that BIR3 domain XIAP where caspase-9 Smac proteins bind an attractive site designing small-molecule inhibitors XIAP. Through computational structure-based screening in-house traditional herbal medicine three-dimensional structure database 8221...
Bcl-2 belongs to a growing family of proteins which regulates programmed cell death (apoptosis). Overexpression has been observed in 70% breast cancer, 30−60% prostate 80% B-cell lymphomas, 90% colorectal adenocarcinomas, and many other forms cancer. Thereby, is an attractive new anti-cancer target. Herein, we describe the discovery novel classes small-molecule inhibitors targeted at BH3 binding pocket Bcl-2. The three-dimensional (3D) structure modeled on basis high-resolution NMR solution...
A structure-based approach was employed to design a new class of small-molecule inhibitors Bcl-2. The most potent compound 5 (TW-37) binds Bcl-2 with Ki value 290 nM and also Bcl-xL Mcl-1 high affinities. Compound potently inhibits cell growth in PC-3 prostate cancer cells an IC50 200 effectively induces apoptosis dose-dependent manner.
Microtubule-disrupting agents such as the taxanes comprise some of most clinically useful chemotherapeutic and invoke spindle checkpoint in proliferating cells. A robust turn may forestall mitotic catastrophe, potentially providing a mechanism that permits cancer cells to survive transient exposure these drugs. Previous reports on G2-M cell cycle progression by histone deacetylase inhibitors suggested potential role modulating therapeutic efficacy microtubule-disrupting agents. As both...
We report herein the design of potent and orally active small-molecule inhibitors MDM2−p53 interaction. Compound 5 binds to MDM2 with a Ki 0.6 nM, activates p53 at concentrations as low 40 potently selectively inhibits cell growth in tumor cells wild-type over mutated/deleted p53. has good oral bioavailability effectively SJSA-1 xenograft model.
<h3>Background</h3> Programmed death-1 (PD-1) immune checkpoint blockade has achieved clinical successes in cancer therapy. However, the response rate of anti-PD-1 agents remains low. Additionally, a subpopulation patients developed hyperprogressive disease upon PD-1 Combination therapy with targeted may improve immunotherapy. Recent studies show that p53 activation myeloid linage suppresses alternative (M2) macrophage polarization, and attenuates tumor development invasion, leading to...
The hematogenous metastatic pattern of gastric cancer (GC) was not fully explored. Here we analyzed the frequency and clinicopathological features metastasis to liver, lung, bone, brain from GC patients. Data queried for this analysis included patients Surveillance, Epidemiology, End Results Program database 2010 2014. All statistical analyses were performed using Intercooled Stata 13.0 (Stata Corporation, College Station, TX). tests two-sided. Totally, there 19 022 eligible analysis. At...
Abstract Background BCR-ABL1 T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib Chinese adults TKI-resistant CML (CML-CP) accelerated (CML-AP). Methods 1 study, was orally administered once every other day 28-day cycles at 11 dose cohorts ranging from 60 mg, evaluated maximum...
Abstract Background The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial. Methods We conducted a retrospective analysis G/GEJ who had undergone treatment PD-1 between October 2017 and May 2022. primary outcomes were objective response rate (ORR) progression-free survival (PFS). SPSS software V27.0 was used for...
Angiopoietin-1 (Ang-1) and its receptor Tie-2, a trans-membrane tyrosine kinase uniquely expressed by endothelial cells, are shown null mutation studies to be essential developmental angiogenesis. The phenotypic abnormalities in these knockout animals suggest that Tie-2 signaling is necessary for the maintenance expansion of primitive capillary network. We present vitro evidence indicating Ang-1/Tie-2 system participates regulation tubule formation survival confluent cells. Although...
Abstract Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function others are regulated by tumor suppressor P53, which plays pivotal role in leukemogenesis. Opposing P53-mediated activities mouse double minute 2 homolog (MDM2), promotes P53 degradation. Because TP53...
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...
Abstract The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to immunosuppressive tumor microenvironment and lack sufficient infiltration activated CD8+ T cells. Transforming (TME) from “cold” “hot” thus more likely potentiate effects ICIs is a promising strategy for cancer treatment. We found that selective BCL-2 inhibitor APG-2575 can enhance antitumor efficacy anti-PD-1 therapy syngeneic humanized CD34+ mouse models. Using single-cell RNA sequencing, we...
11502 Background: SDH-deficient GIST is a rare type of GIST, mainly observed in the stomach children and adolescents or young adults < 30 years age. No active targeted therapies have been identified this subset GIST. Olverembatinib, approved China for treatment patients with chronic myeloid leukemia, has shown promising clinical efficacy We report here updated data preliminary paraganglioma, which an SDH-deficient–related tumor. Methods: The aim study was to evaluate safety (per RECIST...
The lymphotoxin-beta receptor (LT beta R) is a tumor necrosis factor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LT R monoclonal antibody (mAb) CBE11 inhibited growth in xenograft models potentiated responses to chemotherapeutic agents. In syngeneic colon carcinoma model, treatment tumor-bearing mice with an against murine LT caused increased lymphocyte infiltration tumor. A pattern differential gene...