Therapeutic peptidomimetic macrocycles

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...

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Benefits of technology

[0007]The invention also provides a method of treating cancer in a human patient in need thereof comprising administering to the patient a peptidomimetic macrocycle, wherein the cancer is colon cancer. In one embodiment, the peptidomimetic macrocycle comprises an α-helix. In another embodiment, the peptidomimetic macrocycle comprises a BH3 domain. 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. In some embodiments, the cancer is at least 2-fold less sensitive to treatment using a corresponding cross-linked BIM polypeptide as measured in an in vitro cell viability assay. In other embodiments, the cancer is at least 5-fold less sensitive to treatment using a corresponding cross-linked BIM polypeptide as measured in an in vitro cell viability assay. In yet other embodiments, the cancer is at least 8-fold less sensitive to treatment using a corresponding cross-linked BIM polypeptide as measured in an in vitro cell viability assay.

[0008]Also provided is a method of treating cancer in a human patient in need thereof comprising administering to the patient a peptidomimetic macrocycle wherein said peptidomimetic macrocycle shows an EC50 lower than about 5 μM when tested in an in vitro cell viability assay against a cell line derived from said cancer. In some embodiments, the EC50 may be lower than about 4 μM. In other embodiments, the EC50 may be lower than about 3 μM. In yet other embodiments, the EC50 may be lower than about 2 μM. In yet other embodiments, the EC50 may be lower than about 1 μM. In some embodiments, the in vitro assay is performed in the presence of serum. For example, the assay may be performed in 10% human serum. In some aspects, the cancer is selected from the group consisting of ovarian cancer, skin cancer, prostate cancer, renal cancer, breast cancer, pancreatic cancer, small-cell lung cancer, colon cancer, multiple myeloma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL) of T cell lineage or B cell lineage or mixed lineage, chronic lymphocytic leukemia (CLL), cutaneous T cell lymphoma (CTCL), acute myelocytic leukemia (AML), chronic myelocytic leukemia, and follicular lymphoma.

[0009]In one aspect, the present invention provides a method of treating cancer in a human patient in need thereof comprising administering to the patient a peptidomimetic macrocycle, wherein the cancer is selected from the group consisting of ovarian cancer, prostate cancer, renal cancer, breast cancer, pancreatic cancer, and Ph+ acute lymphocytic leukemia. In one embodiment, the peptidomimetic macrocycle comprises an α-helix. In another embodiment, the peptidomimetic macrocycle comprises a BH3 domain. The peptidomimetic macrocycle can 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.

[0010]In some embodiments, the cancer is selected from the group consisting of colon cancer, small-cell lung cancer, liver cancer, ovarian cancer, skin cancer, prostate cancer, renal cancer, breast cancer, pancreatic cancer, glioma, multiple myeloma, Burkitt's lymphoma, acute lymphocytic leukemia (ALL) of T cell lineage or B cell lineage or mixed lineage, chronic lymphocytic leukemia (CLL), cutaneous T cell lymphoma (CTCL), acute myelocytic leukemia (AML), chronic myelocytic leukemia and follicular lymphoma. In one embodiment, the peptidomimetic macrocycle comprises an α-helix. In another embodiment, the peptidomimetic macrocycle comprises a BH3 domain. 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% identic

Problems solved by technology

Despite decades of intense research efforts in this area, the treatment of cell proliferative disorders remains a challenge.

Ther

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