A5030967968- Cytokine Signaling Pathways and Interactions
- Mathematical Biology Tumor Growth
- Protein Degradation and Inhibitors
- Monoclonal and Polyclonal Antibodies Research
- Microtubule and mitosis dynamics
- Multiple Myeloma Research and Treatments
- Prostate Cancer Treatment and Research
- Cancer, Hypoxia, and Metabolism
- Radiopharmaceutical Chemistry and Applications
- Angiogenesis and VEGF in Cancer
- Chronic Myeloid Leukemia Treatments
- Computational Drug Discovery Methods
- Glycosylation and Glycoproteins Research
- Histone Deacetylase Inhibitors Research
- HER2/EGFR in Cancer Research
- Nanoparticle-Based Drug Delivery
- Click Chemistry and Applications
- RNA Interference and Gene Delivery
- Acute Myeloid Leukemia Research
- Receptor Mechanisms and Signaling
- Chronic Lymphocytic Leukemia Research
- Dendrimers and Hyperbranched Polymers
- Cancer-related gene regulation
- DNA Repair Mechanisms
- Cell Adhesion Molecules Research
AstraZeneca (United States)
2007-2023
Kala Pharmaceuticals (United States)
2023
AstraZeneca (United Kingdom)
2009-2022
Guangdong University of Technology
2022
AstraZeneca (Sweden)
2013
AnaBios (United States)
2010
Millennium Engineering and Integration (United States)
2005
Cold Spring Harbor Laboratory
2001
Indiana University – Purdue University Indianapolis
2001
Children's Hospital of Los Angeles
2001
Mutations of the tumor suppressor PTEN, a phosphatase with specificity for 3-phosphorylated inositol phospholipids, accompany progression brain tumors from benign to most malignant forms. Tumor progression, particularly in aggressive and tumors, is associated induction angiogenesis, process termed angiogenic switch. Therefore, we tested whether PTEN regulates by modulating angiogenesis. U87MG glioma cells stably reconstituted cDNA were growth nude mouse orthotopic model. We observed that...
Localized angiopoietin-2 (Ang2) expression has been shown to function as a key regulator of blood vessel remodeling and tumor angiogenesis, making it an attractive candidate for antiangiogenic therapy. A fully human monoclonal antibody (3.19.3) was developed, which may have significant pharmaceutical advantages over synthetic peptide-based approaches in terms reduced immunogenicity increased half-life block Ang2 function. The 3.19.3 potently binds with equilibrium dissociation constant 86...
The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Pharmacological targeting bromodomains by small molecule inhibitors has proven be an effective means disrupt aberrant programs critical for tumor growth and/or survival. Herein, we report AZD5153, a potent, selective, orally available BET/BRD4 inhibitor possessing bivalent binding mode. Unlike previously described monovalent...
Abstract Dual Bcl-2/Bcl-x L inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a potent dual inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design development of AZD0466, drug-dendrimer conjugate, where...
Abstract MLN2704 is an antibody-chemotherapeutic conjugate designed to target prostate-specific membrane antigen (PSMA). PSMA a transmembrane receptor whose expression largely restricted prostatic epithelium and prostate cancer cells with its level increasing during the progression of malignancy. consists de-immunized, monoclonal antibody that specific for conjugated drug maytansinoid 1 (DM1), microtubule-depolymerizing compound. After binding subsequent cellular internalization this...
Abstract Purpose: Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, had success the clinic, another member, Bcl-xL, also target and mechanism resistance. Therefore, we developed dual Bcl-2/Bcl-xL inhibitor that broadens therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia. Experimental Design: We used structure-based chemistry to design small-molecule Bcl-xL...
Barasertib (AZD1152), a highly potent and selective aurora kinase B inhibitor, gave promising clinical activity in elderly acute myeloid leukemia (AML) patients. However, utility was limited by the requirement for 7-day infusion. Here we assessed potential of nanoparticle formulation Aurora inhibitor AZD2811 (formerly known as AZD1152-hQPA) preclinical models AML. When administered to HL-60 tumor xenografts at single dose between 25 98.7 mg/kg, treatment delivered profound inhibition growth,...
Abstract The Poly (ADP-ribose) polymerase (PARP) family has numerous essential functions in cellular processes such as transcription, chromatin remodelling, DNA damage response and repair well apoptosis. PARP inhibition blocks base excision results conversion of SSBs to double-strand break (DSBs). DSBs are the most deleterious form that can be generated by exogenous damaging agents or endogenous replication stress. repaired homologous recombination (HRR) non-homologous end joining (NHEJ)....
Prostate cancer bone metastasis is distinguished by the predominance of osteoblastic lesions. This phenotype has been difficult to reproduce in animal models. Here, we describe a model utilizing 22Rv1 human prostate cell line that generates osteolytic lesions and prominent spiculated periosteal response following intraosseous injection scid mice.We injected 22Rv1-luciferase cells directly into tibiae C.B-17 mice. We analyzed tumor growth pathology every 2 weeks using radiographic histologic...
Platelet-derived growth factor receptor <i>α</i> (PDGFR<i>α</i>) is a tyrosine kinase that promotes cell survival and expressed in both the tumor stromal components of human cancers. We have developed fully monoclonal antibody, MEDI-575, selectively binds to PDGFR<i>α</i> with high affinity, no observable affinity for murine PDGFR<i>α</i>. To more characterize role regulation stroma, we evaluated vivo antitumor effects MEDI-575 tumor-bearing severe combined immunodeficient (SCID) mice...
Barasertib (AZD1152), a pro-drug of the highly potent and selective Aurora B kinase inhibitor AZD2811, showed promising clinical activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients administered as 4-day infusion. To improve potential therapeutic benefit inhibition, nanoparticle formulation AZD2811 has been developed to address limitations repeated intravenous One challenges with use nanoparticles for chronic treatment tumors is optimizing dose schedule required...
Abstract The induction of apoptosis in tumor cells represents a promising approach to the treatment cancer. In cells, B cell lymphoma 2 (Bcl-2) protein family promotes survival through upregulation anti-apoptotic Bcl-2 proteins, such as Bcl-2, Bcl-xL, Mcl-1 and Bcl-w. Clinical activity inhibitor venetoclax has validated targeting this class molecules, but additional value remains jointly with other members. AZD0466 is novel drug-dendrimer conjugate, where active moiety, AZD4320, chemically...
Abstract Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to highly potent topoisomerase I (TOP1) inhibitor payload via stable, tumor-selective, tetrapeptide-based cleavable linker. Despite its promising early clinical signals, drug resistance challenge that may emerge with time. The mechanisms Dato-DXd are currently unknown. Herein, we created and investigated novel models characterize...
6521 Background: To improve on outcomes achieved with OFAR1 in CLL/RS (Tsimberidou et al J Clin Oncol 26:196), we designed OFAR2 (phase I/II). Methods: consisted of oxaliplatin 30 mg/m2 D1-4; fludarabine mg/m2; Ara- C 0.5 g/m2; rituximab 375 D3; and pelfigrastim 6 mg D6. Fludarabine Ara-C were given D2-3 (level 1), D2-4 2), or D2-5 3) I) every 4 wks. Tumor lysis, DNA virus, PCP prophylaxis given. Results: Overall, 94 pts (CLL, 67; RS, 27) treated. DLT occurred 2/3 at level 3 (G4 diarrhea G4...
Abstract Dual Bcl-2/Bcl-xL inhibitors are expected to deliver therapeutic benefit in many hematological and solid tumors, but their clinical application has been limited by tolerability issues, including thrombocytopenia. AZD4320, a potent dual inhibitor, showed good efficacy encountered dose limiting cardiovascular toxicity preclinical species, had challenging physicochemical properties which prevented its development. Nanocarriers can provide prolonged circulation time, controlled release,...
Abstract The bromodomain and extraterminal (BET) protein BRD4 regulates gene expression via recruitment of transcriptional regulatory complexes to acetylated chromatin. Across a number tumor models pharmacological targeting bromodomains by small-molecule inhibitors has proven be an effective means disrupt aberrant programs. Herein, we report AZD5153, potent, selective, orally available BET/BRD4 inhibitor. AZD5153 is candidate drug that possesses unprecedented bivalent binding mode among...
Abstract A nanoparticle formulation of AZD2811, a selective aurora kinase B inhibitor, is currently under clinical development for the treatment both haematological and solid tumour disease. AZD2811 active derivative prodrug Barasertib (AZD1152) which gave promising activity in elderly AML patients delivered as 7-day infusion (Kantarjian et al, Cancer, 119, 2611-2619, 2013). To address limitations associated with utility other cell cycle inhibitors clinic, has been incorporated into an...
Phosphorylation of xenobiotics is rare, probably owing to a strong evolutionary pressure against it. This rarity may have attracted more attention recently as result intentionally designed kinase-substrate analogs that depend on kinase-catalyzed activation form phosphorylated active drugs. We report rare metabolite observed unexpectedly in mouse plasma samples after an oral dose Tankyrase inhibitor was not intended be kinase substrate, i.e.,...
Abstract The Poly (ADP-ribose) polymerase (PARP) family has numerous essential functions in cellular processes such as transcription, chromatin remodelling, DNA damage response and repair well apoptosis. PARP inhibition blocks base excision results conversion of SSBs to double-strand break (DSBs), the most deleterious form damage. DSBs can be repaired by homologous recombination (HRR) or non-homologous end joining (NHEJ). physiological importance HRR is underscored observation genomic...