Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo
| Autor: | Richard Wooster, Beata Sweryda-Krawiec, Benoît Moreau, Rossitza G. Alargova, Michelle DuPont, Patrick Lim Soo, Rajesh Shinde, James M. Quinn, Patrick Rosaire Bazinet, Gitanjali Sharma, Kerry Whalen, Tsun Au Yeung, Mark T. Bilodeau, Charles-Andre Lemelin, Kristina Kriksciukaite, Brian H. White, Adam Brockman, Samantha Perino, Haley Oller |
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| Rok vydání: | 2019 |
| Předmět: |
Agonist
Immunoconjugates medicine.drug_class CHO Cells Maytansinoid 01 natural sciences Cell Line 03 medical and health sciences chemistry.chemical_compound Mice Cricetulus Dogs In vivo Drug Discovery medicine Somatostatin receptor 2 Animals Humans Maytansine Receptors Somatostatin Receptor 030304 developmental biology 0303 health sciences Drug discovery Antineoplastic Agents Phytogenic Xenograft Model Antitumor Assays In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Cancer research Molecular Medicine Conjugate |
| Zdroj: | Journal of medicinal chemistry. 62(5) |
| ISSN: | 1520-4804 |
| Popis: | Somatostatin receptor 2 (SSTR2) is frequently overexpressed on several types of solid tumors, including neuroendocrine tumors and small-cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized upon binding to the receptor and linking a toxic payload to an SSTR2 agonist is a potential method to kill SSTR2-expressing tumor cells. Herein, we describe our efforts towards an efficacious SSTR2-targeting cytotoxic conjugate; examination of different SSTR2-targeting ligands, conjugation sites, and payloads led to the discovery of 22 (PEN-221), a conjugate consisting of microtubule-targeting agent DM1 linked to the C-terminal side chain of Tyr3–octreotate. PEN-221 demonstrates in vitro activity which is both potent (IC50 = 10 nM) and receptor-dependent (IC50 shifts 90-fold upon receptor blockade). PEN-221 targets high levels of DM1 to SSTR2-expressing xenograft tumors, which has led to tumor regressions in several SSTR2-expressing xenograft mouse models. The safety and efficacy of PEN-221 is currently ... |
| Databáze: | OpenAIRE |
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