Treatment for tumors driven by metabolic dysfunction
Inventors
Shanahan, James • Cornelius, Peter
Assignees
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Publication Number
US-11273142-B2
Publication Date
2022-03-15
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 relates to a method of treating cancer in a subject in need thereof by determining at least one of body mass index (BMI), waist/hip circumference ratio (WHR), or HOMA score and comparing at least one of the subject’s BMI, WHR, or HOMA score to a corresponding predetermined cutoff value. The subject is determined to have at least one metabolic dysfunction when at least one of the BMI, WHR, or HOMA score is greater than the predetermined cutoff value.
After identifying metabolic dysfunction, the method administers to the subject at least one therapeutically effective amount of at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug, or analog thereof. The polymer conjugate comprises a Formula with independently variable groups including R4, R5, R6, Z, AA1-AA6, L, Q, X, M, J, Y, W, and parameter ranges for x, y, n, p, q, and r.
Within the Formula, Z is defined as either 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, and W is a Methionine aminopeptidase 2 (MetAP2) inhibitor moiety or alkyl. The construct includes amino-acid residue-derived elements together with a MetAP2 inhibitor moiety for treating cancer.
Claims Coverage
The independent claim set centers on three main inventive features: metabolic dysfunction determination using BMI, WHR, or HOMA compared to predetermined cutoffs; determination of metabolic dysfunction when the metric is greater than the cutoff; and administration of a therapeutically effective amount of a polymer conjugate defined by a detailed Formula that includes a MetAP2 inhibitor moiety.
Metabolic dysfunction determination using BMI, WHR, or HOMA cutoffs
Determining at least one of body mass index (BMI), waist/hip circumference ratio (WHR), or HOMA score of the subject; comparing at least one of the subject's BMI, WHR, or HOMA score to a corresponding predetermined cutoff value; determining that the subject has at least one metabolic dysfunction when at least one of the subject's BMI, WHR, or HOMA score is greater than the predetermined cutoff value.
Administration of a therapeutically effective MetAP2 inhibitor polymer conjugate
Administering to the subject having the at least one metabolic dysfunction at least one therapeutically effective amount of at least one polymer conjugate, or a pharmaceutically acceptable salt, prodrug or analog thereof, wherein the at least one polymer conjugate comprises the Formula with W being a Methionine aminopeptidase 2 (MetAP2) inhibitor moiety or alkyl.
Defined linker architecture and constrained substituent selections
Defining the polymer conjugate by structural variables including R4, R5, R6, Z, AA1-AA6, L, Q, X, M, J, Y, and parameter ranges for x, y, n, p, q, and r, with Z including 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.
Overall, the claim coverage ties cancer treatment to identification of metabolic dysfunction by BMI, WHR, or HOMA cutoff comparison and to administration of a structurally defined polymer conjugate containing a MetAP2 inhibitor moiety.
Stated Advantages
Enhanced therapeutic index.
Lower toxicity.
Reduced dosing frequency and dose amounts.
Improved metabolic biomarker profile.
Reduced tumor growth/metastasis.
Increased survival.
Decreased mortality.
Selectivity/non-cytotoxicity to normal cells.
Intracellular delivery is advantageous when released small molecules bind intracellular targets with high affinity and/or high on-rates relative to efflux.
Linker cleavage leaving a linker fragment attached to the active moiety can reduce efflux by altering properties such as MW, hydrophobicity, PSA, and charge.
The described approach can influence cell efficacy by modifying the pharmacokinetic profile relevant to intracellular behavior.
Documented Applications
Treating cancer in a subject in need thereof by determining BMI, WHR, or HOMA score, identifying metabolic dysfunction based on predetermined cutoff values, and administering a polymer conjugate that includes a MetAP2 inhibitor moiety.
Treating post-menopausal HR+/Her2− breast cancer and other listed solid and hematologic cancers.
Clinical evaluation in a Phase 1 clinical trial of compound 1 in advanced refractory/late-stage solid tumors, with endpoints including safety/tolerability, MTD/RP2D, pharmacokinetics/pharmacodynamics, imaging, and biomarker endpoints such as MetAP2 and leptin/adiponectin and leptin:adiponectin ratio.
Phase 1 biomarker examples reporting metabolic dysfunction biomarker improvements in patients across multiple cancer types, including carcinoid, colon, endometrial, cervical, and hormone receptor-positive breast cancer.
Treating cancer in a subject having metabolic dysfunction identified by BMI, WHR, or HOMA score above a predetermined cutoff, using a MetAP2 inhibitor polymer conjugate (compound 1) as described in preclinical obesity-accelerated tumor models (B16F10 melanoma and E0771 mammary tumors).
In vivo testing comparing Compound 1 versus Compound 4/CKD-732 beloranib in DIO B16F10 melanoma mice, including measurements of tumor effects, body weight change, adipose tissue mass, white blood cell count, and lung metastases.
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