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Targeted therapeutics

a targeted, therapeutic technology, applied in the direction of biocide, drug composition, instruments, etc., can solve the problems of unsatisfactory current therapeutics and therapies, limited applicability and/or effectiveness of chemotherapy, and limited side effects of other therapies and diagnostics employing potentially toxic moieties, so as to facilitate an additive or synergistic

Inactive Publication Date: 2014-03-20
SYNTA PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a way to target therapy, making it more effective and minimizing side effects. The size and chemical properties of the SDC-TRAP allow it to passively diffuse or be actively transported into cells with intracellular targets of interest. Additionally, the SDC-TRAP can deliver a cytotoxic molecule to destroy target cells, such as cancer or inflammatory cells.

Problems solved by technology

Although tremendous advances have been made in chemotherapy, currently available therapeutics and therapies remain unsatisfactory and the prognosis for the majority of patients diagnosed with chemotherapeutically treated diseases (e.g., cancer) remains poor.
Often, the applicability and / or effectiveness of chemotherapy, as well as other therapies and diagnostics employing potentially toxic moieties, is limited by undesired side effects.
In some cases, the presence of these high levels of protein is caused by overexpression.
In addition, because the environment of a tumor is typically hostile due to hypoxia, nutrient deprivation, acidosis, etc., tumor cells may be especially dependent on Hsp90 for survival.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

examples

[0355]The following examples, which are briefly summarized and then discussed in turn below, are offered by way of illustration and not by way of limitation.

[0356]Example 1 presents the synthesis of exemplary SDC-TRAPs.

[0357]Example 2 presents the targeted delivery of exemplary SDC-TRAPs.

[0358]Example 3 presents an exemplary assay for selecting binding moieties.

[0359]Example 4 presents the cytotoxicity of exemplary SDC-TRAPs.

[0360]Example 5 presents the stability of exemplary SDC-TRAPs in plasma.

[0361]Example 6 presents a detailed schematic for the synthesis of an exemplary SDC-TRAP.

[0362]Example 7 presents results of tests using the SDC-TRAP of Example 6.

[0363]Example 8 presents the synthesis and testing of a lenalidomide-based SDC-TRAP.

[0364]Examples 9 and 10 present examples of IC50 value determinations.

[0365]Example 11 presents an exemplary Hsp90α binding assay.

[0366]Example 12 presents an exemplary HER2 degradation assay.

[0367]Example 13 presents an exemplary cytotoxicity assay...

example 1

[0375]SDC-TRAPs of an exemplary embodiment may be prepared in following manner:

[0376]The synthesis of Compound 1 and Compound 3 are discussed in WO 2007 / 139968 and WO 2004 / 012661, respectively.

[0377]Synthesis of Compound 2 (STEP-1): To a solution of 1.0 g (2.48 mmols) of compound 1 in 60 mL of 1:1:1-Methanol:Tetrahydrofuran:Acetic acid was added 75 mg of 10% Palladium on charcoal (wet Degussa type) and the contents of the flask was deoxygenated by vacuum and hydrogen purge. It was then pressurized to 60 Psi with hydrogen and stirred for 5 h at room temperature. The flask was then thoroughly flushed with argon and filtered the solids through a short pad of celite. Evaporation and recrystallization of the crude product afforded 900 mg (88%) of the compound 2 in pure form as off white solid. ESMS calculated for C23H28N4O3: 408.22. Found: 409.1 (M+).

[0378]Synthesis of the Conjugate 1: To a stirred solution of 0.1 g (0.245 mmols) of Compound 2 in 5 mL of anhydrous N,N-Dimethylformamide w...

example 2

[0450]The ability of Hsp90-targeting moieties to penetrate solid tumors and exhibit rapid clearance from normal tissues for reduced toxicity is illustrated in the following tissue distribution study with a compound, ganetespib, which may be used as an Hsp90 binding moiety.

[0451]Tissue Distribution of ganetespib in Female CD-1 nu / nu Mice Bearing RERF Human NSCLC Xenografts

[0452]Objectives:

[0453]To confirm the distribution of ganetespib in blood, livers, kidneys, brains, hearts, lungs and tumors after IV administration of ganetespib to female CD-1 nu / nu mice bearing RERF human NSCLC xenografts, and to examine metabolic profiles of ganetespib in plasma, red blood cells, and above tissues.

[0454]Study Outline:

[0455]Test Articles: ganetespib

Animals: female CD-1 nu / nu mice bearing RERF human NSCLC xenografts (N=3 / group)

Route: IV

[0456]Dosage: 50 mg / kg

Dose level: 10 mL / kg

Formulation: 10% DMSO, 18% Cremophor RH40, 3.6% dextrose solution (DRD)

Bleeding time points: 5 min, 6, 24 hr

Collected tiss...

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Abstract

The present invention provides pharmacological compounds including an effector moiety conjugated to an binding moiety that directs the effector moiety to a biological target of interest. Likewise, the present invention provides compositions, kits, and methods (e.g., therapeutic, diagnostic, and imaging) including the compounds. The compounds can be described as a protein interacting binding moiety-drug conjugate (SDC-TRAP) compounds, which include a protein interacting binding moiety and an effector moiety. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the effector moiety.

Description

RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Patent Application No. 61 / 624,639, filed on Apr. 16, 2012. The contents of this application are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The present invention relates to pharmacological compounds including an effector moiety conjugated to an binding moiety that directs the effector moiety to a biological target of interest. The compounds have broad pharmacological applications including therapeutics, diagnostics, and imaging. For example, the compounds can specifically direct therapeutic effector moieties to target cells or tissue of interest, for targeted chemotherapeutic treatment of conditions such as cancer.BACKGROUND OF THE INVENTION[0003]Although tremendous advances have been made in chemotherapy, currently available therapeutics and therapies remain unsatisfactory and the prognosis for the majority of patients diagnosed with chemotherapeutically treated disease...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48A61K31/4745A61K31/454G01N33/574A61K31/513A61K31/58A61K31/4184A61K31/704A61K31/4196A61K31/185
CPCA61K47/481A61K31/4196A61K31/4745A61K31/454A61K31/185A61K31/513A61K31/58A61K31/4184A61K31/704G01N33/57496A61K47/54A61K47/545A61K47/55A61P35/00G01N33/574A61K31/437A61K31/496A61K31/506A61K31/519A61K31/565A61K31/167A61K31/4545A61K47/50
Inventor CHIMMANAMADA, DINESH U.YING, WEIWEN
Owner SYNTA PHARMA CORP
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