Delmar Pharmaceuticals, Inc.

Del Mar Pharmaceuticals (Bc) Ltd.

Matrix Pharmaceutical, Inc.

Chemgenex Pharmaceuticals, Inc.

Other

Matrix Pharmaceuticals, Inc.

Chemgenex Therapeutics, Inc.

Oncogen

Valent Technologies LLC

Matrix Pharmaceutical, Inc./project Hear

Teva Pharmaceuticals International Gmbh

Dennis M Brown

Jeffrey A Bacha

Edward E Luck

Anne Steinø

Sandra Dunn

William J Garner

Richard E Jones

Mike Tso-Ping Li

Daniel R Twardzik

Richard Schwartz

Anthony F Purchio

Richard Maskiewicz

Shaun Fouse

Ian Nisbet

David H Sierra

Anne Steino

Shawnya K Michaels

Saira Singh

Kent C Shih

Sarath Kanekal

Howard A Burris, Iii

Shawnya Michaels

Sareth Kanekal

Howard A Burris

The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to mustard-based alkylating agents such as uracil mustard and analogs, derivatives, or prodrugs thereof, including 6-methyluracil mustard and 6-ethyluracil mustard.

Therapeutic benefit of suboptimally administered chemical compounds

Methods for treating diffuse intrinsic pontine glioma (DIPG) comprising administration of a therapeutically effective amount of an alkylating hexitol (such as dianhydrogalacitol, diacetyldianhydrogalacitol, and dibromodulcitol) are disclosed. Such methods may further comprise administration of other anti-cancer agents. In preferred embodiments, the secondary anti-cancer agent is an inhibitor of Wee1 tyrosine kinase (such as adavosertib). Methods of treating malignancies in general comprising administration of a combination of an alkylating hexitol and an inhibitor of Wee1 tyrosine kinase are also disclosed.

Dianhydrogalactitol for the treatment of diffuse intrinsic pontine gliomas

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of non-small-cell lung carcinoma (NSCLC) and ovarian cancer, as well as other types of malignancy, including brain metastases of NSCLC. Dianhydrogalactitol acts as an alkylating agent on DNA that creates Nmethylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents and can possess additive or super-additive effects.

Use of dianhydrogalactitol and analogs or derivatives thereof in combination with platinum-containing antineoplastic agents to treat non-small-cell carcinoma of the lung and brain metastases

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of malignancies of the central nervous system in pediatric patients, including glioblastoma multiforme (GBM) high grade glioma, and medulloblastoma. Dianhydrogalactitol acts as an alkylating agent on DNA that creates Nmethylation and that can induce double-stranded breaks in DNA. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide, cisplatin, and tyrosine kinase inhibitors; the drug acts independently of the MGMT repair mechanism. Dianhydrogalactitol can be used together with other anti-neoplastic agents (e.g. cisplatin) and can possess additive or super-additive effects.

Use of dianhydrogalactitol or derivatives or analogs thereof for treatment of pediatric central nervous system malignancies

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of glioblastoma multiforme and medulloblastoma. Dianhydrogalactitol acts as an alkylating agent on DNA that creates N7 methylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide; the drug acts independently of the MGMT repair mechanism.

Use of substituted hexitols including dianhydrogalactitol and analogs to treat neoplastic disease and cancer stem cells including glioblastoma multiforme and medulloblastoma

Methods and compositions suitable for the treatment of malignancies such as recurrent glioma and progressive secondary brain tumor are disclosed. These methods employ a hexitol derivative such as dianhydrogalactitol, a derivative or analog of dianhydrogalactitol, diacetyldianhydrogalactitol, or a derivative or analog of diacetyldianhydrogalactitol. The compositions can include such hexitol derivatives.

Use of dianhydrogalactitol and analogs and derivatives thereof to treat recurrent malignant glioma or progressive secondary brain tumor

The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutically active agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo. In particular, the therapeutically active agents selected from the group consisting of: (i) indirubin; (ii) an analog of indirubin; (iii) a derivative of indirubin or of an analog of indirubin; and (iv) a pharmaceutical composition comprising indirubin, an analog of indirubin, or a derivative of indirubin or of an analog of indirubin, especially meisoindigo, are effective Nek9 inhibitors. The active agent, such as meisoindigo, can act as a Nek9 inhibitor. The active agent can be used together with Nek9 inhibitors or agents that inhibit the expression of Nek9.

Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo

Use of substituted hexitols including dianhydrogalactitol and analogs to treat neoplastic disease and cancer stem and cancer stem cells including glioblastoma multiforme and medulloblastoma

The invention relates to novel molecules and libraries thereof as well as methods for their production. Methods of producing the novel molecules include the cleaving of starting molecules into molecular subunits and the assembly of the subunits into novel recombined molecules.

Recombined molecules and preparation thereof

The present invention describes methods and compositions for improving the therapeutic efficacy of therapeutic agents previously limited by suboptimal therapeutic performance by either improving efficacy as monotherapy or reducing side effects. Such methods and compositions are particularly applicable to substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol.

Compositions to improve the therapeutic benefit of suboptimally administered chemical compounds including substituted hexitols such as dianhydrogalactitol and diacetyldianhydrogalactitol

The present invention is directed to methods for treatment of malignancies in companion animals employing dianhydrogalactitol, diacetyldianhydrogalactitol, and dibromodulcitol, as well as analogs and derivatives thereof, in addition to a method to improve the efficacy and/or reduce the side effects of the administration of a therapeutic agent selected from the group consisting of dianhydrogalactitol, a derivative of dianhydrogalactitol, diacetyldianhydrogalactitol, a derivative of diacetyldianhydrogalactitol, dibromodulcitol, and a derivative of dibromodulcitol to a veterinary subject, the method comprising the steps of: (1 (identifying at least one factor or parameter associated with the efficacy and/or occurrence of side effects of the administration of the therapeutic agent to the veterinary subject; and (2) modifying the factor or parameter to improve the efficacy and/or reduce the side effects of the administration of the therapeutic agent to the veterinary subject.

Veterinary use of dianhydrogalactitol, diacetyldianhydrogalactitol, and dibromodulcitol to treat malignancies

The use of dianhydrogalactitol provides a novel therapeutic modality for the treatment of glioblastoma multiforme. Dianhydrogalactitol acts as an alkylating agent on DNA that creates Nmethylation. Dianhydrogalactitol is effective in suppressing the growth of cancer stem cells and is active against tumors that are refractory to temozolomide; the drug acts independently of the MGMT repair mechanism.

Use of dianhydrogalactitol and analogs and derivatives thereof to treat glioblastoma multiforme

The present invention provides an efficient method of synthesizing and purifying dianhydrohexitols such as dianhydrogalactitol. In general, as applied to dianhydrogalactitol, the method comprises: (1) reacting dulcitol with a concentrated solution of hydrobromic acid at a temperature of about 80&#xb0; C. to produce dibromogalactitol; (2) reacting the dibromogalactitol with potassium carbonate in t-butanol to produce dianhydrogalactitol; and (3) purifying the dianhydrogalactitol using a slurry of ethyl ether to produce purified dianhydrogalactitol. Another method produces dianhydrogalactitol from dulcitol; this method comprises: (1) reacting dulcitol with a reactant to convert the 1,6-hydroxy groups of dulcitol to an effective leaving group to generate an intermediate; and (2) reacting the intermediate with an inorganic weak base to produce dianhydrogalactitol through an intramolecular S2 reaction. Other methods for the synthesis of dianhydrogalactitol from dulcitol are described.

Method of synthesis of substituted hexitols such as dianhydrogalactitol

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Menlo Park, CA, United States of America

Dennis M Brown