STONY BROOK, NY, United States
STONY BROOK, NY, United States

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Patent
New York University and Chem-Master International, Inc | Date: 2016-12-19

This invention provides a compound having the structure wherein , , X, Y, and R_(1)-R_(11 )are defined herein. This invention also provides a pharmaceutical composition comprising the above compounds, a method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP), a method of inhibiting the production of a cytokine in a population of cells, a method of inhibiting the production of a growth factor in a population of cells, and a method of inhibiting NF-B activation in a population of cells.


MacKenzie G.G.,State University of New York at Stony Brook | Sun Y.,State University of New York at Stony Brook | Huang L.,State University of New York at Stony Brook | Xie G.,State University of New York at Stony Brook | And 6 more authors.
Gastroenterology | Year: 2010

Background & Aims Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective cancer chemopreventive agents. However, chronic administration of NSAIDs is associated with significant side effects, mainly of the gastrointestinal tract. Given these limitations, we synthesized phospho-sulindac (P-S; OXT-328), a novel sulindac derivative. Methods Here, we evaluated the safety and efficacy of P-S in preclinical models, including its mechanism of action with human colon cancer cell (HCCC) lines and animal tumor models. Results (1) Compared with sulindac, P-S is much more potent in inhibiting the growth of cultured HCCCs and more efficacious in preventing the growth of HT-29 xenografts in nude mice. P-S also prevents the growth of intestinal tumors in Apc/Min mice. (2) In combination with difluoromethylornithine (DFMO), P-S reduced tumor multiplicity in Apc/Min mice by 90%. (3) P-S is much safer than sulindac as evidenced by its in vitro toxicologic evaluation and animal toxicity studies. Mechanistically, P-S increases the intracellular levels of reactive oxygen and nitrogen species, which are key early mediators of its chemopreventive effect. Moreover, P-S induces spermidine/spermine N 1-acetyltransferase enzymatic activity, and together with DFMO it reduces polyamine levels in vitro and in vivo. Conclusions P-S displays considerable safety and efficacy, two pharmacologic properties that are essential for a potential cancer chemopreventive agent, and thus merits further evaluation. © 2010 AGA Institute.


PubMed | Chem-Master International, Inc, Lixte Biotechnology Holdings, Theradex Systems Inc., City of Hope Comprehensive Cancer Center and 3 more.
Type: | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

To determine the maximum tolerated dose and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors.LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3+3 dose-escalation design.There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was re-enrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1mg/m2 level. Probable or possible study drug-related Grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n=2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for 4 or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles which was maintained for 5 additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n=2), and prostate cancer. The recommended phase 2 dose of LB-100 is 2.33mg/m2 daily for 3 days every 3 weeks.The safety, tolerability, preliminary evidence of anti-tumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies.


The present invention provides a method of inhibiting the growth of or promoting differentiation and destruction of cancer stem cells (CSCs) comprising contacting the cancer stem cells with a compound having the structure: or a pharmaceutically acceptable salt thereof.


Patent
New York University and Chem-Master International, Inc | Date: 2016-08-18

This invention provides a compound having the structure wherein , , A, B, and R_(1)-R_(4 )are defined herein. This invention also provides pharmaceutical compositions comprising the above compounds, a method of accelerating the healing of a wound, a method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP), a method of inhibiting the production of a cytokine in a population of cells, a method of inhibiting the production of a growth factor in a population of cells, and a method of inhibiting NF-B activation in a population of cells.


Patent
New York University and Chem-Master International, Inc | Date: 2014-09-05

The present invention provides a method of inhibiting the binding of anthrax lethal factor with protective antigen comprising contacting the anthrax lethal factor with a compound having the structure:


Patent
New York University and Chem-Master International, Inc | Date: 2015-10-14

This invention provides a compound having the structure wherein , , X, Y, and R_(1)-R_(11 )are defined herein. This invention also provides a pharmaceutical composition comprising the above compounds, a method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP), a method of inhibiting the production of a cytokine in a population of cells, a method of inhibiting the production of a growth factor in a population of cells, and a method of inhibiting NF-B activation in a population of cells.


Patent
New York University and Chem-Master International, Inc | Date: 2012-10-16

This invention provides a compound having the structure wherein , , A, B, and R_(1)-R_(4 )are defined herein. This invention also provides pharmaceutical compositions comprising the above compounds, a method of accelerating the healing of a wound, a method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP), a method of inhibiting the production of a cytokine in a population of cells, a method of inhibiting the production of a growth factor in a population of cells, and a method of inhibiting NF-B activation in a population of cells.


The present invention provides a method of inhibiting the growth of or promoting differentiation and destruction of cancer stem cells (CSCs) comprising contacting the cancer stem cells with a compound having the structure: or a pharmaceutically acceptable salt thereof.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 2.67M | Year: 2010

DESCRIPTION (provided by applicant): An unmet need in the area of cytotoxic therapy for human cancer is the development of an agent that is highly effective, yet is relatively safe with respect to side effects. The use of most chemotherapeutic drugs in human cancer treatment is accompanied by a variety of side effects including hair loss, corrugated and twisted nail formation and hemorrhage of the mucosa of the alimentary canal. The attractive aspects of DHA-SBT-1214 are its ability to target tumor cells then, once absorbed, release the cytotoxic taxoid moiety where it will do the most damage. This is the innovative aspect of this drug development program. Such a drug should readily find a place in the armamentarium of anti-tumor drug substances. With minimal side effects, it should also lend itself commercially to combination therapy in conjunction with an anti-tumor enzyme regulator, as is becoming the common practice in modern cancer treatment. Chem-Master's mission is to develop DHA-SB-T-1214 as efficacious and safer drug for cancer chemotherapy, especially against tumors that cannot effectively be treated by Taxol(R), docetaxel, Taxoprexin(R), and other commonly used chemotherapeutic drugs. In the SBIR Phase I study, we have made significant progress toward this goal. We have confirmed that the chemical synthesis of DHA-SBT-1214 with high purity is feasible at 10 g scale based on the proposed synthetic route. We have also confirmed the remarkable efficacy of DHA- SBT-1214 against pancreatic cancer (CFPAC-1) and non-small cell lung cancer (H460) xenografts in SCID mice models in addition to highly drug-resistant (Pgp+) colon cancer (DLD-1) xenograft as well as significant activity against another highly drug-resistant (Pgp+) breast cancer (LCC6-MDR) xenograft, wherein Taxol(R) and Taxoprexin(R) showed very limited activity or totally inactive. The project proposed in this Phase II application is designed to advance our studies on DHA-SBT-1214 to treat a variety of human tumors principally associated with colon, breast, lung and pancreatic cancers as well as to perform pre-clinical toxicology studies required for IDN filing and approval. Thus, the key technical objectives in the Phase II studies are (i) further expansion of the current studies to cancer cell lines that are more refractory to other cytotoxic agents and/or to faster growing tumors; (ii) Pharmacokinetics/pharmacodynamics (PK/PD) studies including half-life, distribution, metabolism and maximum tolerated dose, as well as all other pre-clinical toxicology studies necessary for IND filing; (iii) optimization of the preparative methods in 200 g scale for the reliable production of DHA-SBT-1214 in GMP and the development of validation methods for the various intermediates in the synthetic sequence. PUBLIC HEALTH RELEVANCE: The proposed project is of great relevance to human health. Currently there are no really effective drug substances that can abolish or even partially inhibit the growth of human colon cancer because this particular form of cancer over-expresses the MDR phenotype. Remarkably DHA-SBT-1214, an omega-3 fatty acid- taxoid conjugate, can penetrate these cancer cells selectively and by-pass the MDR apparatus, thereafter inducing cell death. The further development of DHA-SBT-1214 as a possible treatment for colon, pancreatic, lung, breast and other forms of cancer could scarcely be more relevant in a society where many forms of this multi-variate and largely untreatable disease, seem to be increasing.

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