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1.
Bioorg Med Chem Lett ; 98: 129573, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38052377

RESUMEN

In this study, we present a modular synthesis and evaluation of two prostate-specific membrane antigen (PSMA) targeted small molecule drug conjugates (SMDCs) incorporating the potent chemotherapeutic agent monomethyl auristatin E (MMAE). These SMDCs are distinguished by their cleavable linker modules: one utilizing the widely known valine-citrulline linker, susceptible to cleavage by cathepsin B, and the other featuring a novel acid-labile phosphoramidate-based (PhosAm) linker. Both SMDCs maintained nanomolar affinity to PSMA. Furthermore, we confirmed the selective release of the payload and observed chemotherapeutic efficacy specifically within PSMA-positive prostate cancer cells, while maintaining cell viability in PSMA-negative cells. These findings not only validate the efficacy of our approach but also highlight the potential of the innovative pH-responsive PhosAm linker. This study contributes significantly to the field and also paves the way for future advancements in targeted cancer therapy.


Asunto(s)
Antineoplásicos , Inmunoconjugados , Neoplasias de la Próstata , Humanos , Masculino , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Citrulina , Sistemas de Liberación de Medicamentos , Inmunoconjugados/uso terapéutico , Valina , Neoplasias de la Próstata/tratamiento farmacológico
3.
Tetrahedron Lett ; 61(41)2020 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-33191958

RESUMEN

In this work, we developed a novel "click"-ready pH-cleavable phosphoramidate linker for controlled-release of monomethyl auristantin E (MMAE) in antibody- and small molecule-drug conjugates application. This water-soluble linker was found to have tremendous stability at physiological pHs while rapidly releasing its payload at acidic pH. The linker can also be tailored to release payloads of diverse functional groups, broadening its applications.

4.
Mol Cancer Ther ; 21(11): 1701-1709, 2022 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-35999662

RESUMEN

New targeted chemotherapeutics are urgently needed to minimize off-target toxicity and reduce the high-mortality rate associated with metastatic prostate cancer. Herein, we report on the modular synthesis, pharmacokinetics, and efficacy of two small-molecule-drug conjugates (SMDC) targeted to prostate-specific membrane antigen (PSMA) incorporating either: (i) a cathepsin-B-cleavable valine-citrulline (Val-Cit), or (ii) an acid-cleavable phosphoramidate linker. Crucial components used in the design of the conjugates include: (i) CTT1298, a nanomolar affinity ligand that binds irreversibly to PSMA and has proven in past studies to rapidly internalize and shuttle payloads into PSMA-expressing prostate cancer cells, (ii) MMAE, a known potent cytotoxic payload, and (iii) an albumin-binder, proven to improve residence time of drug conjugates. At dose of 0.8 mg/kg (∼250 nmol/kg), the two SMDCs showed significant efficacy in a PSMA(+) PC3-PIP mouse model of human prostate cancer compared with controls, without inducing systemic toxicity. Though localization of the SMDCs was observed in tissues apart from the tumor, release of MMAE was observed predominantly in tumor tissue, at levels that were 2-3 orders of magnitude higher than non-target tissues. Furthermore, SMDC2, which incorporated a novel pH-responsive phosporamidate linker, demonstrated significantly improved efficacy over SMDC1 that has a Val-Cit linker, with a 100% survival over 90 days and 4 out of 8 mice showing complete tumor growth inhibition after 6 weekly doses of 0.8 mg/kg (244 nmol/kg). Our findings demonstrate the potential of irreversible PSMA inhibitors combined with pH-responsive linkers as a way to specifically deliver chemotherapeutic drugs to prostate cancer tumors with minimal toxicity.


Asunto(s)
Antineoplásicos , Neoplasias de la Próstata , Masculino , Animales , Humanos , Ratones , Línea Celular Tumoral , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Neoplasias de la Próstata/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Albúminas/uso terapéutico
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