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1.
Bioorg Med Chem Lett ; 50: 128335, 2021 10 15.
Article in English | MEDLINE | ID: mdl-34425201

ABSTRACT

Fulvestrant is an FDA-approved drug with a dual mechanism of action (MOA), acting as a full antagonist and degrader of the estrogen receptor protein. A significant limitation of fulvestrant is the dosing regimen required for efficacy. Due to its high lipophilicity and poor pharmacokinetic profile, fulvestrant needs to be administered through intramuscular injections which leads to injection site soreness. This route of administration also limits the dose and target occupancy in patients. We envisioned a best-in-class molecule that would function with the same dual MOA as fulvestrant, but with improved physicochemical properties and would be orally bioavailable. Herein we report our progress toward that goal, resulting in a new lead GNE-502 which addressed some of the liabilities of our previously reported lead molecule GNE-149.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Breast Neoplasms/drug therapy , Drug Discovery , Receptors, Estrogen/metabolism , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Dose-Response Relationship, Drug , Female , Humans , MCF-7 Cells , Mice , Molecular Structure , Protein Conformation , Xenograft Model Antitumor Assays
2.
Bioorg Med Chem Lett ; 30(4): 126907, 2020 02 15.
Article in English | MEDLINE | ID: mdl-31902710

ABSTRACT

Chimeric molecules which effect intracellular degradation of target proteins via E3 ligase-mediated ubiquitination (e.g., PROTACs) are currently of high interest in medicinal chemistry. However, these entities are relatively large compounds that often possess molecular characteristics which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. Accordingly, we explored whether conjugation of chimeric degraders to monoclonal antibodies using technologies originally developed for cytotoxic payloads might provide alternate delivery options for these novel agents. In this report we describe the construction of several degrader-antibody conjugates comprised of two distinct ERα-targeting degrader entities and three independent ADC linker modalities. We subsequently demonstrate the antigen-dependent delivery to MCF7-neo/HER2 cells of the degrader payloads that are incorporated into these conjugates. We also provide evidence for efficient intracellular degrader release from one of the employed linkers. In addition, preliminary data are described which suggest that reasonably favorable in vivo stability properties are associated with the linkers utilized to construct the degrader conjugates.


Subject(s)
Antibodies, Monoclonal/immunology , Drug Carriers/chemistry , Estrogen Receptor alpha/immunology , Antibodies, Monoclonal/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/immunology , Antineoplastic Agents/pharmacology , Drug Design , Estrogen Receptor alpha/metabolism , Humans , Immunoconjugates/chemistry , Immunoconjugates/immunology , Immunoconjugates/pharmacology , MCF-7 Cells , Proteolysis/drug effects , Receptor, ErbB-2/metabolism
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