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Therapeutic peptidomimetic macrocycles

a technology of peptidomimetic macrocycles and macrocycles, which is applied in the direction of peptide/protein ingredients, metabolism disorders, immunological disorders, etc., can solve the problems of limited side effects, side effects, cost, and difficulty in treating cell proliferative disorders, so as to reduce the risk of cancer survival, less sensitive to treatment, and less sensitive to treatment

Inactive Publication Date: 2009-11-05
AILERON THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]In another aspect, the invention provides a method of treating an immunoproliferative disorder in a human patient in need thereof comprising administering to the patient a peptidomimetic macrocycle. The peptidomimetic macrocycle may reduce activated hPBL proliferation by more than about 5%, 10%, 20%, 30%, 40%, or 50% in an in vitro BrdU incorporation assay. The immunoproliferative disease may be, for example, a lymphoproliferative disorder, or an autoimmune disease, for example, systemic lupus erythematosus. The peptidomimetic macrocycle can be, for example, a BID polypeptide. In some cases, an amino acid sequence of the BID polypeptide is more than about 60% identical to a sequence DIIRNIARHLA*VGD*NleDRSI and wherein * is a tethered amino acid and Nle is norleucine. Alternatively, an amino acid sequence of the BID polypeptide is more than about 80% identical to a sequence-DIIRNIARHLA*VGD*NleDRSI wherein * is a tethered amino acid and Nle is norleucine. Furthermore, an amino acid sequence of said BID polypeptide may be more than about 95% identical to a sequence DIIRNIARHLA*VGD*NleDRSI wherein * is a tethered amino acid and Nle is norleucine. The peptidomimetic macrocycle may also be, for example, a BIM polypeptide. In some cases, an amino acid sequence of the BIM polypeptide is more than about 60% identical to an amino acid sequence IWIAQELR*IGD*FNAYYARR wherein * is a tethered amino acid. Alternatively, the amino acid sequence of the BIM polypeptide is more than about 80% identical to an amino acid sequence IWIAQELR*IGD*FNAYYARR wherein * is a tethered amino acid. Furthermore, an amino acid sequence of said BIM polypeptide may be more than about 95% identical to an amino acid sequence IWIAQELR*IGD*FNAYYARR wherein * is a tethered amino acid.

Problems solved by technology

Despite decades of intense research efforts in this area, the treatment of cell proliferative disorders remains a challenge.
Therapeutic methods for cancer such as surgery or chemotherapy are still limited in terms of efficacy, side effect profile and cost.

Method used

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  • Therapeutic peptidomimetic macrocycles
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  • Therapeutic peptidomimetic macrocycles

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Peptidomimetic Macrocycles of the Invention

[0343]α-helical BID and BIM peptidomimetic macrocycles were synthesized, purified and analyzed as previously described (Walensky et al (2004) Science 305:1466-70; Walensky et al (2006) Mol Cell 24:199-210) and as indicated below. The macrocycles used in this study are shown below. The corresponding uncrosslinked polypeptides are indicated as “WT Sequence” and represent the natural counterparts of the peptidomimetic macrocycles of the invention.

Calculat-Calcu-FoundMacro-WTed m / zlated m / zm / zcycleSequenceSequence(M + H)(M + 3H)(M + 3H)SP-1BID-BH3Ac-DIIRNIARHLA$VGD$NleDRSI-NH22438.40813.47813.7SP-2BID-BH3Ac-DIIRNIARHLA$VED$NleDRSI-NH22510.42837.48837.25SP-3BID-BH3Ac-DIIRNIARHLAQVGDSNleDRSI-NH22403.32801.78801.89SP-4BIM-BH3Ac-IWIAQELR$IGD$FNAYYARR-NH22646.43882.82883.15SP-5BIM-BH3Ac-IWIAQELR$IED$FNAYYARR-NH22718.45906.82906.9SP-6BIM-BH3Ac-IWIAQELRRIGDEFNAYYARR-NH22681.41894.47894.69SP-7BID-BH3Pr-RNIARHLA$VAibD$NleDRSI-NH22139.25713....

example 2

Cell Viability Assays

[0348]Cell viability assays shown in FIGS. 1-32 were performed according to the following protocol. Tumor cell lines were grown in specific serum-supplemented media (growth media) as necessary. A day prior to the initiation of the study, cells were plated at optimal cell density (15,000 to 25,000 cells / well) in 200 μl growth media in microtiter plates. The next day, cells were washed twice in serum-free / phenol red-free RPMI complete media (assay buffer) and a final volume of 100 μl assay buffer was added to each well. Human peripheral blood lymphocytes (hPBLs) were isolated from Buffy coats (San Diego Blood Bank) using Ficoll-Paque gradient separation and plated on the day of the experiment at 25,000 cells / well.

[0349]Peptidomimetic macrocycles were diluted from 1 mM stocks (100% DMSO) in sterile water to prepare 400 μM working solutions. The peptidomimetic macrocycles and controls were then diluted 10 or 40 fold or alternatively serially two-fold diluted in assa...

example 3

BrdU Cell Proliferation Assay

[0356]hPBLs isolated from two different donors were stimulated or not with 5 μg / ml PHA, 1 μM Ionomycin and 1 μg / ml LPS and treated with either 5 or 20 μM of SP-1 in assay buffer. 1 μM Rapamycin was used as a positive control to inhibit BrdU incorporation. The cells were incubated for 48 hrs under the conditions indicated in FIG. 17. BrdU incorporation was assayed by ELISA according to manufacturer's instructions (Roche, catalog number 11444611001). In FIG. 7, the Y axis shows OD=Absorbance (A405 nm / A492 nm.)

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Abstract

The present invention provides biologically active peptidomimetic macrocycles for the treatment of cell proliferative disorders such as cancer and immunoproliferative disease.

Description

CROSS-REFERENCE[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 027,326 filed 8 Feb. 2008 and U.S. Provisional Application No. 61 / 120,380 filed 5 Dec. 2008, each of which applications is incorporated herein in its entirety by reference.BACKGROUND OF THE INVENTION[0002]Uncontrolled cell proliferation is implicated in a wide number of disorders ranging from cancer to immunoproliferative diseases. For example, in the U.S. alone, cancer surpasses heart disease as the leading cause of death for the largest fraction of the population (Journal of the National Cancer Institute, Vol. 97, No. 5, Mar. 2, 2005, p. 330) and contributes to more than 500,000 deaths annually. Despite decades of intense research efforts in this area, the treatment of cell proliferative disorders remains a challenge.[0003]Therapeutic methods for cancer such as surgery or chemotherapy are still limited in terms of efficacy, side effect profile and cost. In particular, the efficacy and a...

Claims

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Application Information

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IPC IPC(8): A61K38/16A61P35/00
CPCA61K38/12C07K7/64A61K45/06A61K38/1761A61P3/00A61P35/00A61P35/02A61P37/02A61K38/00
Inventor NASH, HUW M.ANNIS, DAVID ALLENKAPELLER-LIBERMANN, ROSANASAWYER, TOMI K.KAWAHATA, NORIYUKIHAN, JIAWEN
Owner AILERON THERAPEUTICS INC
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