Treatment for tumors driven by metabolic dysfunction
Inventors
Shanahan, James • Cornelius, Peter
Assignees
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Publication Number
US-10646463-B2
Publication Date
2020-05-12
Expiration Date
Abstract
The present disclosure relates to modified or polymer conjugated MetAP2 inhibitors. The present disclosure also relates to methods of treating metabolically-driven diseases and disorders, such as certain cancers.
Core Innovation
The invention provides a method for treating, or ameliorating at least one symptom of, cancer in a subject in need thereof by administering a therapeutically effective amount of at least one polymer conjugate. The polymer conjugate comprises a defined chemical formula with independently varying substituents and structural components, including R4, R5, R6, Z, and a linker and inhibitor moiety portion, and includes a Methionine aminopeptidase 2 (MetAP2) inhibitor moiety as W or an alkyl.
The Z segment is constructed from amino-acid units AA1 through AA6 linked to C(O) groups and a C(O)-Q-X-Y-C(O)-W arrangement, with AA1 selected from glycine, alanine, or H2N(CH2)mCO2H and AA2 through AA6 selected from bonds or specified amino acids. The polymer conjugate further includes variable linker components through L, Q, X, Y, M, J, V, and additional variable definitions including R9, R10, R11, x, y, n, p, q, and r, which define a family of polymer-conjugate molecules.
The method is applied to multiple cancer types, including post-menopausal HR+/Her2− breast cancer, esophageal carcinoma, esophageal adenocarcinoma, cancer of the tongue, colorectal adenocarcinoma, gastro-intestinal stromal tumor (GIST), cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gall bladder cancer, cholangiocarcinoma, liver cancer, clear-cell renal cancer, melanoma, multiple myeloma, thyroid cancer, or combinations thereof. The subject is characterized by excessive visceral adiposity, elevated leptin levels, depressed adiponectin levels, a high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, or any combination thereof.
Claims Coverage
The consolidated claim coverage reflects one independent method claim. The claim centers on administering a therapeutically effective amount of a structurally defined polymer conjugate containing a MetAP2 inhibitor moiety, with two core inventive feature groups: the conjugate structure and the specified cancer/subject treatment context.
Method of treating cancer with a defined polymer conjugate
Administering a therapeutically effective amount of at least one polymer conjugate comprising a specified formula to treat, or ameliorate at least one symptom of, cancer in a subject in need thereof.
Polymer conjugate with MetAP2 inhibitor moiety and defined Z segment
The polymer conjugate includes a MetAP2 inhibitor moiety as W or an alkyl, and Z is defined as NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-L or NH-AA1-AA2-AA3-AA4-AA5-AA6-C(O)-Q-X-Y-C(O)-W, with AA1 through AA6 selected from specified amino acids or bonds and with defined linker components L, Q, X, Y, M, J, V, R9, R10, R11, and parameter ranges x, y, n, p, q, and r.
Cancer treatment in subjects with specified metabolic dysfunction
Treating cancer in a subject with excessive visceral adiposity, elevated leptin levels, depressed adiponectin levels, a high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, or any combination thereof, for specified cancer types including post-menopausal HR+/Her2− breast cancer and additional listed cancers.
Overall, the claim coverage is directed to a cancer-treatment method using a polymer conjugate with a defined amino-acid-based linker architecture and a MetAP2 inhibitor moiety, applied to specified cancers and subject metabolic profiles.
Stated Advantages
Improved therapeutic index relative to parent drugs.
Reduced dosing frequency.
Reduced systemic exposure compared with parent drugs.
Reduced toxicity versus parent drugs.
Documented Applications
Treating, or ameliorating at least one symptom of cancer in a subject in need thereof by administering a polymer conjugate comprising a MetAP2 inhibitor moiety.
Treatment of post-menopausal HR+/Her2− breast cancer, esophageal carcinoma, esophageal adenocarcinoma, cancer of the tongue, colorectal adenocarcinoma, gastro-intestinal stromal tumor (GIST), cervical cancer, endometrial cancer, ovarian cancer, pancreatic cancer, gall bladder cancer, cholangiocarcinoma, liver cancer, clear-cell renal cancer, melanoma, multiple myeloma, thyroid cancer, or combinations thereof.
Treatment in subjects with excessive visceral adiposity, elevated leptin levels, depressed adiponectin levels, a high leptin-to-adiponectin ratio, elevated fasting insulin levels, elevated fasting insulin levels accompanied by chronic inflammation, insulin resistance, or any combination thereof.
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