38 results about "CXCR4 antagonist" patented technology

The current invention provides a method for mobilising endothelial progenitor cells (EPC) and / or mesenchymal stem cells (MSC) in a patient, wherein the method comprises the steps of (i) administering a vascular endothelial growth factor receptor (VEGFR) agonist to the patient; and (ii) administering an antagonist of CXCR4 to the patient. Also provided are uses of EPC and MSC harvested using the methods of the invention.

The invention provides compounds, pharmaceutical compositions and methods of use of certain compounds that are antagonists of the chemokine CXCR4 receptor for the treatment of proliferative conditions mediated by CXCR4 receptors. The compounds provided interfere with the binding of SDF1 to the receptor. These compounds are particularly useful for treating or reducing the severity of hyperproliferative diseases by inhibiting metastasis.

The invention provides compounds, pharmaceutical compositions and methods of use of certain compounds that are antagonists of the chemokine CXCR4 receptor for the treatment of proliferative conditions mediated by CXCR4 receptors. The compounds provided interfere with the binding of SDF1 to the receptor. These compounds are particularly useful for treating or reducing the severity of hyperproliferative diseases by inhibiting metastasis.

In accordance with various aspects of the invention, CXCR4 antagonists may be used to treat hematopoietic cells, such as progenitor or stem cells, to promote the rate of cellular multiplication, self-renewal, proliferation or expansion. CXCR4 antagonists may be used therapeutically to stimulate hematopoietic stem / progenitor cell multiplication / self-renewal.

A composition including a CXCR4 antagonist and a CCR5 antagonist represented by formula I or II: or an acceptable salt, solvate or ester thereof. The CXCR4 antagonist includes at least one of AMD-070, CS-3955, KRH-1120, KRH-2731, and KRH-1636.

Methods to treat or prevent acute kidney injury and chronic kidney injury in subjects using CXCR4 antagonists are disclosed.

The chemokine receptor CXCR4 is a co-receptor for T-tropic strains of HIV-1. A number of small molecule antagonists of CXCR4 are in development, but all are likely to lead to adverse effects due to the physiological function of CXCR4. To prevent these complications, allosteric agonists may be therapeutically useful as adjuvant therapy in combination with small molecule antagonists. A synthetic cDNA library coding for 160,000 different SDF-based peptides was screened for CXCR4 agonist activity in a yeast strain expressing functional receptor. Peptides that activated CXCR4 in an autocrine manner induced colony formation. Two peptides, designated RSVM and ASLW, were identified as novel agonists that are insensitive to the CXCR4 antagonist AMD3100. In chemotaxis assays using the acute lymphoblastic leukemia cell line CCRF-CEM, RSVM behaves as a partial agonist and ASLW as a superagonist. The superagonist activity of ASLW may be related to its inability to induce receptor internalization. In CCRF-CEM cells, the two peptides are also not inhibited by another CXCR4 antagonist, T140, or the neutralizing monoclonal antibodies 12G5 and 44717.111. These results suggest that alternative agonist binding sites are present on CXCR4 that could be screened to develop molecules for therapeutic use.

The present invention generally provides methods for preventing or treating tissue ischemia using CXCR4 antagonists. In one embodiment, the methods include administering to a mammal a therapeutically effective amount of a particular bicylic polyamine to elevate peripheral blood EPCs. The invention has a wide spectrum of applications including reducing or eliminating tissue ishemica associated with a myocardial infarct (heart attack).

The present invention generally provides methods for preventing, treating or reducing the severity of symptoms associated with tissue ischemia by administering a CXCR4 antagonist in combination with at least one nucleic acid encoding a morphogen or effective fragment thereof. In one embodiment, the methods include elevating peripheral blood endothelial progenitor cells (EPCs), bone marrow-derived stem cells (BMSCs), or both cell types. The invention has a wide spectrum of applications including reducing or eliminating tissue ischemia, especially tissue ischemia associated with a myocardial infarct (heart attack).

The invention provides compounds, pharmaceutical compositions and methods of use of certain compounds that are antagonists of the chemokine CXCR4 receptor for the treatment of proliferative conditions mediated by CXCR4 receptors or for the treatment of viral infections. The compounds provided interfere with the binding of SDF 1 to the receptor. These compounds are particularly useful for treating or reducing the severity of hyperproliferative diseases by inhibiting metastasis, or for reducing entry of HIV in to a cell while not reducing the capacity of the stem cells to proliferate. The compounds may be useful for long term treatment regimes.

In accordance with various aspects of the invention, CXCR4 antagonists may be used to treat hematopoietic cells, such as progenitor or stem cells, to promote the rate of cellular multiplication, self-renewal, proliferation or expansion. CXCR4 antagonists may be used therapeutically to stimulate hematopoietic stem / progenitor cell multiplication / self-renewal.

Presently disclosed are methods and compositions for treating or preventing WHIM syndrome and certain other disorders or conditions with a certain CXCR4 antagonist.

The present invention provides a novel treatment which features immune therapy in the context of the functions of MSCs as a novel approach to breast cancer treatment. By identifying and elucidating the role of MSCs in the behavior of breast cancer cells at metastatic sites and also at the primary region, this invention provides novel approaches for therapeutic intervention. More particularly, in the presence of MSCs a CXCR4 antagonist transitioned BCCs into cycling cells and conferred susceptibility to a chemotherapeutic agent. The proliferation of BCCs depended on the release of IL-1α and IL-1β from MSCs, but only if the CXCR4 antagonist uncoupled BCCs from MSCs.

The invention relates to a CXCR4 antagonist recombinant protein SDF-1 Beta P2G as well as a method for the production thereof and applications thereof, comprising: using a specific primer to obtain the SDF-1 Beta P2G cDNA by taking a human SDF-1 Beta cDNA as a template through the site-directed mutagenesis PCR amplification, directly inserting the SDF-1 Beta P2G cDNA into a cloning expression vector pET-30a(+) to construct an SDF-1 Beta P2G / pET-30a(+) recombinant, transforming an Escherichia coli BL21 (DE3), screening positive clones, and preparing the SDF-1 Beta P2G recombinant protein through IPTG induced expression, purification, renaturation, restriction enzyme and high efficiency liquid chromatography separation. The SDF-1 Beta P2G recombinant protein can antagonize a chemotactic factor receptor CXCR4, promote stem cells, angioblasts, etc. to enter peripheral blood from bone marrow, and promote the revascularization and recovering of blood flow of ischemia organs.

Disclosed is a method to recover a mixture cell population consisting of a complete profile of progenitor cells including embryonic like stem cells (a “complete progenitor cell mixture” or CPM) from the peripheral blood of an individual by administering to that individual a combination of at least one or more from the category of growth factors and hormones combining with at least one or more from the category of cell fusion inhibitor compounds, and then recovering peripheral blood progenitor cells from said individual. The hormones and growth factors group should include hGH (human growth hormone) with or without erythropoietin (EPO), but specifically without either G-CSF or GM-CSF. The cell fusion inhibitor group should include a CXCR4 antagonist. Also disclosed is a method for using or preserving such a complete progenitor cells mixture (CPM) for the treatment of diseases.

Mitigating radiation induced injury to a mammal that has been exposed to radiation by administering a pharmaceutically effective amount of a composition comprising at least one CXCR4 antagonist to the mammal.

The present invention provides novel uses for CXCR4 antagonists, including specifically peptides of the T-140 family, in the treatment of skin burns and other injuries. The invention further provides methods for increasing epithelialization in a subject in need thereof, and for preventing or inhibiting fibrosis and excessive scar formation, using peptide inhibitors of the T-140 family as well as other CXCR4 antagonists.

The invention provides compounds represented in formula (I) in the description or pharmaceutically acceptable salts or prodrugs of the compounds. The compounds have novel structure, high efficiency, low toxicity and excellent CXCR4 antagonistic activity, and can block HIV from invading and infecting human target cells, treat or prevent AIDS or mobilize human bone marrow hematopoietic cells, mesenchymal stem cells and stem cells, interfere with CXCL12 / CXCR4 mediated cell migration and adhesion, prevent and treat CXCR4 mediated tumor metastasis, invasion and growth, or block CXCL12 / CXCR4 mediated autoimmune and inflammatory reactions. The compounds can be used as an active ingredient in pharmaceutical composition for preventing and treating HIV in combination with other anti-HIV drugs, or for preventing and treating tumors in combination with other drugs for treating or preventing leukemia, lymphoma, myeloma and solid tumors.

Disclosed is a method to recover a dendritic cell rich mixture from peripheral blood mononuclear cells (PBMC) mobilized with one or more cell adhesion inhibitors (CAI) for the preparation of a dendritic cell vaccine. The CAI derived dendritic cell rich mixture (CdDC) from PBMC can either be used alone or better still, be induced into dendritic vaccine specific preparations with the addition or modification with different antigens and methodologies of immunological induction methods known to the art. These CAI derived dendritic vaccines can then be used, but not exclusively so, in the treatment of cancer and infectious diseases. In order to achieve the best immature and mature dendritic cell rich mixture, peripheral blood cells mobilization may be achieved by administering, simultaneously or in sequence, to an individual one or more of a combination of different chemical compounds, hormones, growth factors etc. prior to PBMC collection with one or more of cell adhesion inhibitors such as a CXCR4 antagonist.

The invention relates to methods and compositions for treating a subject afflicted with a hematological malignancy using a combination of a CXCR4 antagonist and an immunotherapeutic agent.

The invention provides preparing method of the dual targets effect gene mosaic recombinant and application. The method comprises the following steps: using the SDF-54 / R / pET-30a(+) as match plate, augmenting the SDF-54 / R with specificity primer, entering the SDF-54 / R into T-A clone carrier, then in the 3'-SDF-54 / R joining the butt hinge coded sequence of human IgG1 heavy chain antibody and Decorin mature peptide coded sequence, and constructing the SDF-54 / R-IgG1HCHR-Decorin / pMD18-T recombination mosaic. The SDF-54 / R-IgG1HCHR-Decorin keeps the affinity of CXCR4 and losses the intrinsic activity, and suppresses the chemotaxis and transfer activity of wild-type SDF-1ª‡ to breast cancer cell and the growth of breast cancer cell. It can be used as CXCR4 antagonist, at the same time suppressing the growth and transfer of CXCR4 positive tumour cell. So it possesses the dual targets effect.

Provides novel nitrogen-containing compounds with CXCR4 antagonistic activity and therapeutic drugs for diseases such as rheumatism and cancer metastasis based on CXCR4 antagonistic activity. A nitrogen-containing compound represented by the above general formula and a CXCR4 antagonist containing these compounds as an active ingredient. Representative compound has the compound defined as follows in general formula (I): A1, A2 represent guanidino group or the group shown in formula (ia) above, A3 is the monocyclic or polycyclic ring that contains 1 or 2 heteroatoms A heteroaryl ring of the form, B1 is a single bond or an alkylene group, R1 is hydrogen or an alkyl group, W is an alkylene group with 2-3 carbon atoms, a cyclic alkylene group with 5-10 carbon atoms, a carbon atom An aromatic ring with a number of 6-10, a heteroaromatic ring with a carbon number of 5-10, y represents -C(=O)-, x represents -C(=O)-NH-, n1 represents an integer of 1-2, n2 represents an integer of 2-3, and D represents various substituents.

A novel non-peptide CXCR4 antagonist has a low molecular-weight and uses various aromatic compounds, each containing a dipicolylamine-zinc complex. This CXCR4 antagonist finds use, e.g., as an anti-HIV agent, a metastasis inhibitor for a malignant tumor, and a chronic rheumatoid arthritis treatment and / or prevention agent.

The invention relates to a combination of CXCR4 antagonist 6-{4-[1-(Propan-2-yl)piperidin-4-yl]-1,4-diazepan-1-yl}-N-(pyridin-4-yl)pyridine-2-carboxamide and an immune checkpoint inhibitor, and the use of the same in the treatment of tumours and / or cancers.

Haematopoietic stem cell mobilization is a process whereby haematopoietic stem cells are stimulated out of the bone marrow space. Before HSC can mobilize, they must be dislodged and released from the BM stem cell niche in which they reside and are retained by adhesive interactions. Accordingly, in an aspect of the present invention there is provided a method for enhancing dislodgement of HSC and their precursors and progenitors thereof from a BM stem cell binding ligand in vivo or ex vivo, said method comprising administering in vivo or ex vivo an effective amount of an antagonist of an alpha9 integrin or an active portion thereof and a CXCR4 antagonist or an active portion thereof to the BM stem cell niche. Once mobilized to the peripheral blood (PB) the HSC may be collected for transplant. Methods which enhance mobilization of the HSC can also improve treatments of haematological disorders.

The invention relates to a combination of CXCR4 antagonist 6-{4-[1-(Propan-2-yl)piperidin-4-yl]-1, 4-diazepan-1-yl}-N-(pyridin-4-yl)pyridine-2-carboxamide and an immune checkpoint inhibitor, and the use of the same in the treatment of tumours and / or cancers.

The invention herein disclosed provides for compositions, methods for synthesizing said compositions, and methods for using said compositions, wherein the compositions and methods may be used in clinical treatment using hematopoietic transplantation, particularly to those relating to treatment of cancer and metastasis. The compositions regulate mobilization of hematopoietic stem cells (HSCs) between bone marrow (BM) and the peripheral blood (PB).

The present invention proposes a compound represented by formula (I) or a pharmaceutically acceptable salt or prodrug thereof. The compound has a novel structure, high efficiency and low toxicity, and has excellent CXCR4 antagonistic activity, which can block HIV from invading and infecting human target cells or treat or prevent AIDS or mobilize human bone marrow hematopoietic cells, mesenchymal stem cells and stem cells or interfere with CXCL12 / CXCR4-mediated Cell migration and adhesion or prevention, treatment of tumor metastasis, invasion and growth mediated by CXCR4 or block CXCL12 / CXCR4 mediated autoimmunity and inflammatory response; and this type of compound can be used as an effective drug in the pharmaceutical composition The components can be used in combination with other anti-HIV drugs to prevent and treat HIV or in combination with other drugs used for treatment or prevention of leukemia, lymphoma, myeloma and solid tumors to prevent and treat tumors.