Enhanced treatment regimens using mTor inhibitors
Inventors
Liu, Yi • Bui, Lynne • Martin, Michael • Wilson, Troy Edward • Rommel, Christian
Assignees
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Publication Number
US-9174994-B2
Publication Date
2015-11-03
Expiration Date
Abstract
The present invention provides for methods and pharmaceutical compositions comprising inhibitors of mTorC1 and/or mTorC2. In some aspects, the invention provides for treatment regimens resulting in enhanced treatment efficacy and better tolerability.
Core Innovation
The invention relates to a method of treating cancer in a subject in need thereof by administering an mTORC1/mTORC2 inhibitor according to an intermittent regimen. The regimen comprises at least one cycle in which the inhibitor is administered for at least 1 day, followed by an intermission in which the inhibitor is not administered for at least 1 day. The method is directed to cancers including renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, and neck cancer.
The mTORC1/mTORC2 inhibitor is defined by a Formula, or a pharmaceutically acceptable salt thereof, with specified substituent values including E2 is H, X1 is N, X2 is N, W2 is NH, k is 1, R2 is H, and R1 is isopropyl. The disclosure further identifies variable substituent options for the inhibitor scaffold, including V groups such as cyclopropanecarboxamido, cyclopropylamino, morpholinoethylamino, hydroxyethylamino, and N-morpholino, together with additional ring and side-chain embodiments shown in the chemical structures.
The document also describes mTORC1/mTORC2 inhibitor compounds defined by structural Formula I variants, including Formula I-A, I-B, I-B1, I-B2, I-C, I-D, I-E, I-C1, I-C2, I-C1a, and I-C1b, with variable substituents such as X1 through X4, R1 through R9, L, M1, W1/W2, and indices k/j. The disclosed chemistry includes benzothiazolyl-containing heteroaromatic cores and broad substituent classes for alkyl, aryl, and heterocycle substituents.
Claims Coverage
The claim coverage centers on treating cancer with an mTORC1/mTORC2 inhibitor administered on an intermittent regimen, with the inhibitor defined by a specified Formula and fixed substituent values. Independent claim coverage includes the intermittent day-on/day-off cycle and the listed cancer indications; dependent refinements add exposure constraints, a specific 7-day dosing pattern, and administration routes. In total, the provided claim summaries describe three inventive features in the independent claim and additional dependent refinements.
Intermittent administration cycle for mTorC1/mTorC2 inhibitor treatment
Administering an mTorC1/mTorC2 inhibitor to a subject in need thereof according to an intermittent regimen comprising at least one cycle in which the mTorC1/mTorC2 inhibitor is administered for at least 1 day, followed by an intermission in which the mTorC1/mTorC2 inhibitor is not administered for at least 1 day.
Cancer indication coverage for specified malignancies
The method wherein the cancer is selected from renal cancer, renal cell carcinoma, colorectal cancer, uterine sarcoma, endometrial uterine cancer, endometrial cancer, breast cancer, ovarian cancer, cervical cancer, gastric cancer, fibrosarcoma, pancreatic cancer, liver cancer, melanoma, leukemia, myeloma, nasopharyngeal cancer, prostate cancer, lung cancer, glioblastoma, bladder cancer, mesothelioma, head cancer, or neck cancer.
mTorC1/mTorC2 inhibitor defined by a specified Formula
The mTorC1/mTorC2 inhibitor has the Formula, or a pharmaceutically acceptable salt thereof, wherein E2 is H, X1 is N, X2 is N, W2 is NH, k is 1, R2 is H, and R1 is isopropyl.
Specific 7-day intermittent cycle structure
The method includes at least one 7-day cycle in which the mTorC1/mTorC2 inhibitor is given for 5 consecutive days followed by an intermission of 2 consecutive days.
Plasma concentration duration and Cmax constraints
The intermittent regimen is effective to achieve an mTorC1/mTorC2 inhibitor plasma concentration greater than about 100 nM for a duration longer than about 20 hours during a 7-day period of administration, and to achieve a Cmax greater than specified threshold values measured in nM.
Multiple administration routes
The mTorC1/mTorC2 inhibitor is administered using parenteral and oral routes, including intraperitoneally, intravenously, intraarterially, transdermally, intramuscularly, liposomally, via local delivery by catheter or stent, subcutaneously, intraadiposally, and intrathecally.
The claim coverage is directed to intermittent treatment of cancer with a structurally defined mTORC1/mTORC2 inhibitor, and further narrows the method with specific cycle timing, exposure thresholds, and administration routes.
Stated Advantages
Aims for higher or sustained plasma exposure and higher Cmax compared to once-daily dosing.
Maintains or improves pathway inhibition, including reduced phosphorylation of 4EBP1, S6, and/or PRAS40.
Maintains tolerability and avoids grade 3+ adverse events such as rash.
Intermittent regimens yield superior anti-tumor effects versus daily dosing.
Documented Applications
Treating cancer in a subject using an mTORC1/mTORC2 inhibitor with an intermittent regimen.
Treating renal cell carcinoma using the intermittent regimen.
Treating cancer in a subject using an mTorC1/mTorC2 inhibitor administered intermittently with dosing cycles and intermissions.
Use of the intermittent mTorC1/mTorC2 inhibitor method for renal cell carcinoma and the other listed cancer types.
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