Mitogen-activated protein kinase kinase (MEK) degradation compounds and methods of use
Inventors
Jin, Jian • Liu, Jing • Hu, Jianping • Wei, Jieli • Yim, Hyerin • Kabir, Md
Assignees
Icahn School of Medicine at Mount Sinai
Publication Number
US-12103924-B2
Publication Date
2024-10-01
Expiration Date
2041-06-01
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Abstract
This disclosure relates to heterobifunctional compounds (e.g., bi-functional small molecule compounds), compositions comprising one or more of the heterobifunctional compounds, and to methods of use the heterobifunctional compounds for the treatment of certain disease in a subject in need thereof. The disclosure also relates to methods for identifying such heterobifunctional compounds.
Core Innovation
This disclosure relates to heterobifunctional compounds comprising a mitogen-activated protein kinase kinase (MEK) ligand conjugated to a degradation tag through a linker. These compounds, including pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or analogs, are designed to degrade or reduce MEK protein levels. The compounds can bind to MEK proteins that comprise MEK mutants, deletions, or fusion proteins, and may interact with MEK1 and/or MEK2. The MEK ligand moiety can bind to allosteric or ATP-binding sites of MEK and may be selected from various known MEK inhibitors such as PD0316684, Cobimetinib, Trametinib, and others. The degradation tag moiety can bind to ubiquitin ligases, including various E3 ligases such as VHL, cereblon, IAP, MDM2, and others.
The invention addresses the need in the art for compounds, compositions, and methods for the treatment of diseases mediated by MEK. In particular, the disclosed heterobifunctional compounds act as MEK degraders by recruiting E3 ligases to induce degradation of MEK proteins via the ubiquitin-proteasome system, thus potentially diminishing both catalytic and non-catalytic functions of MEK. The compounds may overcome limitations of prior MEK inhibitors, which have issues such as acquired drug resistance.
Claims Coverage
The patent discloses three claims, including one independent claim detailing a heterobifunctional compound, a pharmaceutical composition including that compound, and a method of treating MEK-mediated disease using the compound.
heterobifunctional compound structure
A heterobifunctional compound comprising a MEK ligand conjugated to a degradation tag through a linker, wherein the compound has the defined chemical structure capable of binding MEK and recruiting ubiquitin ligases for MEK degradation.
pharmaceutical composition
A pharmaceutical composition comprising the heterobifunctional compound of the invention along with pharmaceutically acceptable excipients, adjuvants, or vehicles.
method of treating MEK-mediated disease
A method of treating an MEK-mediated disease in a subject by administering a therapeutically effective amount of the heterobifunctional compound of the invention.
The inventive features cover the chemical structure of heterobifunctional compounds designed to degrade MEK, pharmaceutical compositions containing such compounds, and therapeutic methods targeting MEK-mediated diseases via administration of the compounds.
Stated Advantages
The heterobifunctional compounds may provide more profound pharmacological effects than kinase inhibition alone by reducing both catalytic and non-catalytic functions of MEK1/2 proteins.
The compounds potentially delay or overcome acquired drug resistance observed with existing MEK inhibitors.
Some heterobifunctional compounds selectively degrade MEK in MEK-mediated disease cells with higher potency than wild type cells, enabling targeted treatment.
The compounds exhibit potent MEK degradation capability and suppress growth of MEK-mediated cancer cells in vitro and in vivo models.
Documented Applications
Treatment of MEK-mediated diseases including various cancers such as melanoma, colorectal cancer, lung cancer, and hematopoietic cancers.
Treatment of hyperproliferative disorders such as benign hyperplasia, psoriasis, and benign prostatic hypertrophy.
Treatment of inflammatory disorders including ankylosing spondylitis, Crohn's disease, ulcerative colitis, and ischemia reperfusion injuries.
Treatment of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, and alopecia areata.
Treatment of dermatological disorders including atopic dermatitis, pruritus, skin rash, and chronic mucocutaneous candidiasis.
Treatment of other MEK-mediated conditions including viral infections, dry eye disorders, bone remodeling disorders, organ transplant-associated immunological complications, relapsed and refractory cancers.
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