Bicyclic peptide ligands and uses thereof
The present invention provides compounds, compositions thereof, and methods of using the same.
1. A method of inhibiting CAIX or MT1-MMP in a patient or biological sample comprising administering to said patient, or contacting said biological sample with a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of L 1 , L 2 , and L 3 is independently a covalent bond or a C 1-8 bivalent hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by —S—, —N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —S(O)—, —S(O) 2 —or —N(R)CH 2 C(O)—;
each R is independently hydrogen or C 1-4 alkyl;
Scaffold is a trivalent group that connects and orients a cyclic peptide;
Loop A is
and Loop B is
or
Loop A is
and Loop B is
indicates the site of attachment to the N-terminus of the Bicycle;
indicates the site of attachment tothe C-terminus of the Bicycle;
Peptide 1 is hydrogen, or a natural or unnatural amino acid wherein the acid is connected to the N-terminus of the Bicycle via an amide bond;
Peptide 2 is —OH, —NH 2 , or a natural or unnatural amino acid wherein the amino group is connected to the C-terminus of the Bicycle via an amide bond;
each of R 1 and R 2 is independently
each of R 4 is independently hydrogen or C 1-4 aliphatic;
each of n is independently 0 or 1; and
wherein a value of n=0 for R 1 results in a terminal amine, —NH 2 , and a value of n=0 for R 2 results in a terminal carboxamide, —C(O)NH 2 , or a pharmaceutical composition thereof.
2. A method of treating a CAIX-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of L 1 , L 2 , and L 3 is independently a covalent bond or a C 1-8 bivalent hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by —S—, —N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —S(O)—, —S(O) 2 — or —N(R)CH 2 C(0)—;
each R is independently hydrogen or C 1-4 alkyl;
Scaffold is a trivalent group that connects and orients a cyclic peptide;
Loop A is
and Loop B is
indicates the site of attachment to the N-terminus of the Bicycle;
indicates the site of attachment to the C-terminus of the Bicycle;
Peptide 1 is hydrogen, or a natural or unnatural amino acid wherein the acid is connected to the N-terminus of the Bicycle via an amide bond;
Peptide 2 is —OH, —NH 2 , or a natural or unnatural amino acid wherein the amino group is connected to the C-terminus of the Bicycle via an amide bond;
each of R 1 and R 2 is independently
each of R 4 is independently hydrogen or C 1-4 aliphatic;
each of n is independently 0 or 1; and
wherein a value of n=0 for R 1 results in a terminal amine, —NH 2 , and a value of n=0 for R 2 results in a terminal carboxamide, —C(O)NH 2 , or a pharmaceutical composition thereof.
3. A method of treating an MT1-MMP-mediated disorder, disease, or condition in a patient comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of L′, L 2 , and L 3 is independently a covalent bond or a C 1-8 bivalent hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by —S—, —N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —S(O)—, —S(O) 2 —or —N(R)CH 2 C(O)—each R is independently hydrogen or C 1-4 alkyl;
Scaffold is a trivalent group that connects and orients a cyclic peptide;
Loop A is
and Loop B is
indicates the site of attachment tothe N-terminus of the Bicycle;
indicates the site of attachment tothe C-terminus of the Bicycle;
Peptide 1 is hydrogen, ora natural or unnatural amino acid wherein the acid is connected to the N-terminus of the Bicycle via an amide bond;
Peptide 2 is —OH, —NH 2 , or a natural or unnatural amino acid wherein the amino group is connected to the
C-terminus of the Bicycle via an amide bond;
each of R 1 and R 2 is independently each of R 4 is independently hydrogen or C 1-4 aliphatic i each of n is independently 0 or 1 L and wherein a value of n=0 for fil results in a terminal amine, —NH 2 , and a value of n=0 for R 2 results in a terminal carboxamide, —C(O)NH 2 , or a pharmaceutical composition thereof.
4. The method of claim 2 , wherein the CAIX-mediated disorder, disease or condition is selected from the group consisting of a cancer or a proliferative disorder.
5. The method of claim 3 , wherein the MT1-MMP-mediated disorder, disease or condition is selected from the group consisting of a cancer or a proliferative disorder.
6. The method of claim 4 , wherein the cancer or proliferative disorder is selected from the group consisting of tumors of epithelial origin; hematological malignancies and related conditions of lymphoid or myeloid lineage; premalignant hematological disorders and disorders of borderline malignancy; tumors of mesenchymal origin; tumors of the central or peripheral nervous system; endocrine tumors; ocular and adnexal tumors; germ cell and trophoblastic tumors; pediatric and embryonal tumors; and syndromes which leave the patient susceptible to malignancy.
7. The method of claim 5 , wherein the cancer or proliferative disorder is selected from the group consisting of tumors of epithelial origin; hematological malignancies and related conditions of lymphoid or myeloid lineage; premalignant hematological disorders and disorders of borderline malignancy; tumors of mesenchymal origin; tumors of the central or peripheral nervous system; endocrine tumors; ocular and adnexal tumors; germ cell and trophoblastic tumors; pediatric and embryonal tumors; and syndromes which leave the patient susceptible to malignancy.
8. The method of claim 2 , wherein each of L 1 , L 2 , and L 3 is a C 1-8 bivalent hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by —S—, —N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —S(O)—, —S(O) 2 —or —N(R)CH 2 C(O)—.
9. The method of claim 2 , wherein R is hydrogen.
10. The method of claim 2 , wherein Peptide 1 is a natural or unnatural amino acid wherein the acid is connected to the N-terminus of the Bicycle via an amide bond.
11. The method of claim 2 , wherein Peptide 2 is —OH or —NH 2 .
12. The method of claim 2 , wherein R 1 is
13. The method of claim 2 , wherein n=0 for R 2 .
14. The method of claim 3 , wherein each of L 1 , L 2 , and L 3 is a C 1-8 bivalent hydrocarbon chain wherein one, two or three methylene units of the chain are optionally and independently replaced by —S—, —N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —S(O)—, —S(O) 2 —or —N(R)CH 2 C(O)—.
15. The method of claim 3 , wherein R is hydrogen.
16. The method of claim 3 , wherein Peptide 1 is a natural or unnatural amino acid wherein the acid is connected to the N-terminus of the Bicycle via an amide bond.
17. The method of claim 3 , wherein Peptide 2 is —OH or —NH 2 .
18. The method of claim 3 , wherein R 1 is
19. The method of claim 3 , wherein n is 0 for R 2 .
20. The method of claim 3 , wherein Scaffold is
21. The method of claim 1 , wherein Scaffold is
22. The method of claim 2 , wherein Scaffold is
23. The method of claim 6 , wherein:
the tumors of epithelial origin are selected from carcinomas of the bladder and urinary tract, breast, gastrointestinal tract, small intestine, colon, rectum, anus, liver, gall bladder and biliary system, exocrine pancreas, kidney, lung, adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas, mesotheliomas, head and neck, cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity, paranasal sinuses, ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid, adrenal, prostate, skin and adnexae, melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, or dysplastic naevus;
the hematological malignancies are selected from leukemias or lymphomas;
the hematological malignancies and related conditions of lymphoid lineage are selected from acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas and leukemias, natural killer [NK] cell lymphomas, Hodgkin's lymphomas, hairy cell leukemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, or post-transplant lymphoproliferative disorders;
the hematological malignancies and related conditions of myeloid lineage are selected from acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CM ML], hypereosinophilic syndrome, polycythaemia vera, essential thrombocythaemia primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia;
the tumors of mesenchymal origin are sarcomas of soft tissue, bone or cartilage selected from osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumors, benign and malignant histiocytomas, or dermatofibrosarcoma protuberans;
the tumors of the central or peripheral nervous system are selected from astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumors or schwannomas;
the endocrine tumors are selected from pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors or medullary carcinoma of the thyroid;
the ocular and adnexal tumors are retinoblastomas;
the germ cell and trophoblastic tumors are selected from teratomas, seminomas, dysgerminomas, hydatidiform moles or choriocarcinomas;
the pediatric and embryonal tumors are selected from medulloblastoma, neuroblastoma, Wilms tumor, or primitive neuroectodermal tumors; and
the syndromes which leave the patient susceptible to malignancy are Xeroderma Pigmentosum.
24. The method of claim 7 , wherein:
the tumors of epithelial origin are selected from carcinomas of the bladder and urinary tract, breast, gastrointestinal tract, small intestine, colon, rectum, anus, liver, gall bladder and biliary system, exocrine pancreas, kidney, lung, adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas, mesotheliomas, head and neck, cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity, paranasal sinuses, ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid, adrenal, prostate, skin and adnexae, melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, or dysplastic naevus;
the hematological malignancies are selected from leukemias or lymphomas;
the hematological malignancies and related conditions of lymphoid lineage are selected from acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, T-cell lymphomas and leukemias, natural killer [NK] cell lymphomas, Hodgkin's lymphomas, hairy cell leukemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, or post-transplant lymphoproliferative disorders;
the hematological malignancies and related conditions of myeloid lineage are selected from acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, polycythaemia vera, essential thrombocythaemia primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, or promyelocytic leukemia;
the tumors of mesenchymal origin are sarcomas of soft tissue, bone or cartilage selected from osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumors, benign and malignant histiocytomas, or dermatofibrosarcoma protuberans;
the tumors of the central or peripheral nervous system are selected from astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumors or schwannomas;
the endocrine tumors are selected from pituitary tumors, adrenal tumors, islet cell tumors, parathyroid tumors, carcinoid tumors or medullary carcinoma of the thyroid;
the ocular and adnexal tumors are retinoblastomas;
the germ cell and trophoblastic tumors are selected from teratomas, seminomas, dysgerminomas, hydatidiform moles or choriocarcinomas;
the pediatric and embryonal tumors are selected from medulloblastoma, neuroblastoma, Wilms tumor, or primitive neuroectodermal tumors; and
the syndromes which leave the patient susceptible to malignancy are Xeroderma Pigmentosum.
25. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
26. The method of claim 2 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
27. The method of claim 3 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.