Substituted inhibitors of menin-MLL and methods of use
Inventors
Wu, Tao • Li, Liansheng • Wang, Yi • Ren, Pingda • Grembecka, Jolanta • Cierpicki, Tomasz • Klossowski, Szymon • Pollock, Jonathan • Borkin, Dmitry
Assignees
Wellspring Biosciences LLC • University of Michigan System • Kura Oncology Inc
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Publication Number
US-11673898-B2
Publication Date
2023-06-13
Expiration Date
Abstract
The present disclosure provides methods of inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins with compositions of Formula (II-A). The methods are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin. Compositions of Formula (II-A) for use in these methods are also provided.
Core Innovation
The invention relates to compounds of Formula (II-A) and Formula (II) with extensive substituent variables and linker definitions. The compound scope includes C selected from C3-12 carbocycle and 3- to 12-membered heterocycle, linkers L2 and L3 selected from bond and specified carbonyl, sulfur-, nitrogen-, oxygen-, alkylene-, alkenylene-, alkynylene-, and heteroatom-containing groups, and variables m, n, p, R1, R2, R3, RA, RB, RC, R50, R51, R52, R53, R54, R56, R57, and R59.
The disclosure also includes pharmaceutically acceptable salts, isotopic forms, prodrugs, and stereoisomeric forms with enantiomeric excess and diastereomeric excess constraints. The structural definitions permit broad substituent selection, including halogen, nitro, cyano, OR52, SR52, N(R52)2, NR53R54, sulfonyl/sulfone-type groups, carbonyl and phosphoryl-type groups, and ring-forming or bridge-forming relationships among substituents.
The compounds are presented in methods for treating a disease or condition in a subject and for inhibiting an interaction of menin with one or more of MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication. The document also states covalent-binding chemistry in which electrophilic groups form conjugates with menin by reacting with nucleophilic cysteine residues in the menin binding domain.
Claims Coverage
Two independent claims are provided. The claims are centered on a therapeutically effective amount or effective amount of a compound of Formula (II-A) or a pharmaceutically acceptable salt, with extensive structural definitions for C, L2, L3, m, n, p, and substituent variables. The claims diverge in biological purpose: treatment of a disease or condition versus inhibition of menin interactions with MLL-related targets.
Treatment with a Formula (II-A) compound
A method of treating a disease or condition in a subject by administering a therapeutically effective amount of a compound of Formula (II-A) or a pharmaceutically acceptable salt thereof, with defined selections for C, L2, L3, R1, R2, R3, RA, RB, RC, m, n, p, R50, R51, R52, R53, R54, R56, and R59, and with the disease or condition comprising leukemia, hematologic malignancy, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain tumor, or diabetes.
Inhibiting menin interaction with a Formula (II-A) compound
A method of inhibiting an interaction of menin with one or more of MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication by contacting menin with an effective amount of a compound of Formula (II-A) or a pharmaceutically acceptable salt thereof, with the same structural variable framework and stated constraints, including the condition that when R56 is CH3, L3 is not further substituted with OH, NH2, or CN.
Across the independent claims, the inventive coverage is anchored in Formula (II-A) compounds with extensive structural variable definitions and optional stereochemical forms, used either for treating specified diseases or conditions or for inhibiting menin interactions involving MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication.
Stated Advantages
Treating a disease or condition in a subject.
Inhibiting an interaction of menin with one or more of MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication.
Documented Applications
Treating a disease or condition in a subject, where the disease or condition comprises leukemia, hematologic malignancy, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, solid tumor cancer, prostate cancer, breast cancer, liver cancer, brain tumor, or diabetes.
Inhibiting an interaction of menin with one or more of MLL1, MLL2, an MLL fusion protein, and an MLL Partial Tandem Duplication.
Detection of MLL fusion proteins in tumor samples.
Therapeutic use of compounds of Formula (I)/(II) for treating hyperproliferative disorders, including cancers and leukemia with MLL Partial Tandem Duplications/MLL fusions.
Modulating/inhibiting menin interactions with MLL1/MLL2 and MLL fusion proteins.
Chromosome 11q23 rearrangement-mediated disease context.
Combination therapy concepts together with chemotherapeutic agents, targeted inhibitors, and radiation therapy.
In vitro inhibition measurement of menin-MLL binding using fluorescence polarization and HTRF assays.
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